TWI241295B - Pyridazine derivative and medicine containing the same as effect component - Google Patents

Abstract

This invention relates to pyridazine derivatives represented by the formula (1); wherein R1 represents a lower alkoxyl group, a lower alkylthio group or a halogen atom; R2 represents H, a lower alkoxyl group, a lover alkylthio group or a halogen atom; R3 represents a lover alkyl or lower alkenyl group, which may be substituted by one or more OHs, CNs, lower cycloalkyl groups, (substituted) aromatic groups or (substituted) carbamoyl groups; R4 represents COOH, a lower alkoxycarbonyl group, a (substituted) carbamoyl group, a (substituted) amino group, or a (substituted) ureido group; and the dashed line indicates that the carbon-carbon bond between the 4-position and the 5-position is a single bond or a double bond, or salts thereof; and also to medicines containing them as effective ingredients. These compounds have excellent inhibitory activity against interleukin-1beta production, and are useful as preventives and therapeutics for immune system diseases, inflammatory diseases, ischemic diseases and he like.

Description

1241295

Technical scope The present invention relates to a drug having an excellent effect of inhibiting the production of interleukin 3, and is useful for preventing and treating diseases of the immune system, inflammatory diseases, ischemic pyridazine derivatives, and medicines using this as an active ingredient. 'A new background technology Many diseases such as rheumatism, arthritis, osteoporosis, inflammatory bowel disease, immunodeficiency syndrome, sepsis, hepatitis, rickets, blood deficiency disorders, insulin-dependent diabetes, arteriosclerosis, Parkinson's disease Alzheimer's disease, leukemia, is confirmed to be the production of inflammatory cytokines interleukin-1 stone. This interleukin-1 / 3 induces the synthesis of enzymes which are thought to be related to inflammation such as collagenase and PLA2. Injection into animals' joints causes joint destruction very similar to rheumatoid arthritis. On the one hand, the interleukin] point controls its activity through the interleukin q receptor, the soluble interleukin receptor !, and the interleukin] receptor antagonist. For various disease modes, from the studies of gene recombinants, anti-interleukin_1 / 3 antibodies and anti-receptor antibodies using these biological activity inhibitors, and research of using defective mice, understand interleukin_1 / 5 Substances that play an important role in the living body, with an inhibitory effect on interleukin.1 / 3, have become expected to be used as a therapeutic agent for their diseases. For example, among their many diseases, immunosuppressants and steroids used in the treatment of rheumatism have been reported to inhibit interleukins]. Drugs currently under development, such as KE298 (Japanese Inflammation Society (i ihui), 1990), which is a phenylhydrazone propionate derivative, is an immunomodulator and has also been reported to inhibit the production of interleukin. In addition, in a group of compounds known as COX_2 selective inhibitors, for example, fenoxystilbenes, a derivative of phenoxysulfoanilide (dioxin 9b,) -5- This paper size applies Chinese National Standards (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 "Fifth, the description of the invention (2) (DE 2333643) and T-614 (US 49545 18), which is a phenoxybenzopyran derivative, is a double inhibition The agent (C0X-1 / 5-L0) of Tiannidapu (Yuexue 7 V) (oxoxindole derivative) has also been confirmed to inhibit the production of interleukin-1 stone. However, these compounds Either of the effects of inhibiting the production of interleukin-1 / 3 is not the main effect, and has a lower activity than the original effect. In recent years, the synthesis of compounds with the purpose of inhibiting the production of interleukin-1 has been studied. It is greatly increased. As a production inhibitor synthesized by such research, it is classified into a compound group which inhibits the transmission process and translation stage of the nucleus of inflammatory signals and a compound group which inhibits the enzyme ICE, which is a precursor of interleukin-1 / 3/3. As a compound presumed to have the former effect, SB203580 (Special Table) 7-503017), FR167653 (Eur. J. Pharm., 327, 1997, 169-175.), E-5090 (EP376288), CGP47969A (Gastroenterology, 1995, 109, 812-818.), Hydroxyindole derivatives (Eur. J. Med. Chem., 1996, 31, 187-198.) And trispropylpropylpyrrole derivatives (WO97 / 05878), etc .; VE-13,045, which is presumed to have the latter effect, is a peptide compound (Cytokine, 8 (5), 1996, 377-386 ·), etc. However, none of these compounds can sufficiently obtain the effect of interleukin-1 / 3. On the one hand, 5 of the various kinds are known , 6-Diphenylpyridazine derivatives have analgesic and anti-inflammatory effects (EUR. J. MED. CHEM ·, 1979, 14, 53-60), and the substituted 3, 4, 5, and 6-position substituted olfactory derivatives have Inhibitory effect of interleukin-1 / 3 conversion enzyme (Japanese Patent Application Laid-Open No. 7-6 9 8 9 4), etc. However, the inhibitory effect of interleukin-3 -one derivatives substituted at 2, 4, and 6 on interleukin-3- The effect of 1/3 is completely unknown. -6- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7

However, as far as the invention is concerned, the purpose is to provide a compound that exhibits the effect of Paleogene and to use it as an effective formula. The disclosure of the melanin invention is disclosed in such facts. The effect is superior, and it can be used for the prevention and treatment of immune system disorders, inflammation, and leukemia production, and complete the present invention. "The meaning of blood disorders is that the present invention provides the following formula (j) • R1

-R2 (1) (wherein R1 represents a lower alkoxy group, a lower alkylthio group or a halogen atom; r2 represents a fluorene atom, a lower alkoxy group, a lower carbon alkylthio group or a halogen atom; R3 represents 麫Base, halogen atom, cyano, and low-carbon cycloalkyl, as the case may be, are selected from the case: substituted with a base and optionally substituted carbamoyl linear or branched low- or low-carbyl, R4 represents a carboxyl group, a lower alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted thiaminyl group, an optionally substituted amine group, or an optionally substituted ureyl group; the dotted table shows positions 4 and 5 The inter-C bond is a single bond or a double bond) represented by a pyridazine derivative or a salt thereof. In addition, the present invention provides the standard of the paper with the pyridazine derivative (1) or a salt thereof as an active ingredient. The Chinese national standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 4 is provided. The present invention provides a pharmaceutical composition containing the pyridazine derivative (1) or a carrier thereof. The present invention also provides the pyridazine derivative (1) or a salt thereof. F Bureau Medical Music also makes, and in addition, the present invention provides a method for disposing of the pyridazine derivative hydrazone or a salt thereof to treat a disease caused by the hyperproduction of interleukin-1 stone. Best Mode for Carrying Out the Invention The pyridazine derivative of the present invention is represented by the general formula (1). The lower alkoxy group represented by R1 and R2 may be any one of 1-6 to 60, such as methoxymethoxy, propoxy and the like. Examples of the low-carbon alkylthio group include dimethyl, ethylthio, propylthio, and the like. As a prime element, the gas element can be lifted to the atom, bromine atom, iodine atom. "2 as R1 is preferably an F atom, a lower alkoxy group, or a lower alkylthio group, and R is preferably a fluorene atom, a halogen atom, or a lower alkoxy group. Examples include straight chain or branched bonds of 1 to 6C, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, and the like. Also, as low-carbon fluorene | Those branched, more preferably 2 to ^ with 1 to 3 double bonds, such as vinyl, propenyl, butanyl, etc. These lower-carbon alkyl or lower-carbon alkenyl, depending on the case, can be hydroxyl, self-priming Atom, cyano, low-carbon ring, optionally substituted aryl, or optionally substituted carbamoyl. As the low-carbon ring alkyl group, 3 ~ 8 (:, for example, cyclopropyl, cyclobutyl Group, cyclopentyl group, cyclohexyl group, etc. This paper size applies to Chinese National Standard (CNS) A4 specification (2ιχχ 297 public 1241295 A7 ___ __ B7 V. Description of the invention (5) As aryl group 'Contains aromatic hydrocarbon groups and heteroaromatics Examples of the cyclic group include phenyl, naphthyl, pyridinyl, etc., especially phenyl and pyridyl. These aryl groups may optionally have 1 to 3 substituents as this substituent. Examples include a halogen atom, a nitro group, an amine group, and an aryl-substituted carbonylamino group. Herein, as the aryl group substituted on the amine group, there may be mentioned the same aromatic hydrocarbon group or heteroaryl ring group as described above, such as benzene As an optional substituent of a carbamate, a lower alkyl group, a hydroxyl group or an aryl optionally substituted lower alkyl group, and a lower alkylthio group optionally substituted aryl group. 'As a self atom, an aryl group, a low-carbon sulfonyl group, and a low-carbon sulfanyl group, the same as the previous description (including the description of R1 and R2). As R3 is an alkyl group of 1 to 6C or 2 to 9C Low-carbon alkenyl, optionally substituted with mesyl; i element atom; cyano; low-carbon cycloalkyl; or carbonylamino substituted with ～ 3 halogen atoms, nitro, amine or aryl, as appropriate Phenyl or pyridyl; or lower alkyl, hydroxy lower alkyl, aryl-substituted lower alkyl or lower sulfanyl phenyl optionally substituted aminocarbamyl. It is represented by trans 4 Among them, the lower alkoxycarbonyl group is a carboxyl group having an alkoxy group of 1 to 6C, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a butoxycarbonyl group. The substituents of the carbamoyl group or the thiamidine group that are optionally substituted may be substituted lower alkyl groups, aryl groups, etc. that have aryl groups, etc. as the amines that have substituents, as the case may be. Examples of the substituent of the group include a low-carbon alkoxycarbonyl group having a substituent such as an aryl group, a fluorenyl group, and a low-carbon group having a substituent such as an aryl group, and a low-carbon sulfonic acid group. Therefore, as the brewing base, 1 ~ 5C can be cited, such as methyl ethyl, ethyl ethyl, propyl ethyl, butyl ethyl, etc. | __19_ This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 __— —_ B7 V. Description of the invention (6) As a substituent on a ureido group having a substituent as the case may be, a lower alkyl group, etc. In addition, a lower alkyl group, an aryl group, Specific examples of each group such as a lower alkoxy group are the same as those shown in the aforementioned R1, R2, and R3. As R4, a carboxyl group, a lower alkoxycarbonyl group; or a lower alkyl group, an aryl group, or an aryl group optionally substituted with a carbamoyl group or a thiamethane group; or a lower alkoxycarbonyl group, an aromatic group Group substituted lower alkoxycarbonyl, fluorenyl, lower alkyl, aryl substituted lower alkyl or lower alkyl sulfonyl optionally substituted amino; or lower alkyl optionally substituted ureido . It is also preferable that the dotted line portion in the formula (1), that is, those in which C between the 4th and 5th positions are combined to form a double bond. As the pyridazine derivative (1), R1 is an F atom, a lower alkoxy group, or a lower alkylthio group; R2 is a fluorene atom, a halogen atom, or a lower alkoxy group; R3 is a linear or i-6C or A branched low-carbon alkyl group or a straight or branched low-alkenyl group of 2 to 9C. Herein, the alkyl group, halogen atom, cyano group, low-carbon cycloalkyl group, or 1 to 3 halogen atom, nitro group, Amine or aryl substituted carbonylamino optionally substituted phenyl or pyridyl or lower alkyl, hydroxy lower alkyl, aryl substituted lower alkyl or lower alkylthiophenyl optionally substituted aminoformyl Fluorenyl optionally substituted; R4 is carboxy, low-carbon oxycarbonyl or low-carbon alkyl, aryl or aryl substituted low-carbon alkyl optionally substituted carbamoyl or thiocarbamyl or low-carbon alkoxy Carbonyl, aryl substituted low-carbon alkoxycarbonyl, alcohol, low-carbon fluorenyl, aryl-substituted low-carbon alkyl or low-carbon alkyl, optionally substituted amine, or low-carbon alkyl optionally substituted Urea groups are preferred. In addition, 2-isobutyl-6- (4-methoxyphenyl) -4-methylaminemethylmethyl-2H-pyrida-10- __- _______ This paper size applies to China National Standard (CNS) A4 specifications ( 210X 297 mm) 1241295

Qin 3 嗣 2Ό clothing propyl methyl) winter (4-methoxyphenyl) -4-methylamine methyl 2-H-pyridazin-3-one, 2- (¾propylmethyl) winter (3_fluoro_ 4-Methoxyphenylmethylamine formamidine- 2HH3-one, 2- (cyclopropylmethyl) -4_ethylamine methylphenidate · 6 book-methoxybenzene, oral DQQ ^ -one ^ 7 -Chlorocinyl ethoxycarbonylamidotolyl methoxyphenyl) 2 Trenqin-3-one, 2- (4-chlorocinnamyl) · 'methylamido_6_ (4_methoxyphenyl)- 2Η-pyridazine_3-_ and the like are preferred. The salt of the pyridazine derivative (1) of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include hydrochloride, hydrobromide, hydroiodate, sulfate, and nitric acid. Salt, acid addition salt of phosphate, or benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bromate, maleate, rich Acid addition salts of organic acids, such as formate, tartrate, and citrate. In addition, the compound of the present invention may exist in the form of a solvate represented by a hydrate and the form of a keto-enol tautomer, and the solvate and isomer are also included in the present invention. The pyridazine derivative (1) of the present invention can be produced by, for example, the reaction process shown below. -11-This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1241295 A7 B7 V. Description of invention R1

R2

OJ R a

2 R

d 2 R

3 R

\ I / s

2 This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 _______ B7 V. Description of the invention (9) In the case of a lower alkyl or aryl group having a substituent, R8 indicates a lower alkyl group having a substituent as the case, and R9 indicates a lower carbon alkyl group having a substituent as the case 'R1G epithelyl, low-temperature calcination continuation group Or optionally substituted carbamate, X represents 0 atom or S atom, and R1, R2 and R3 have the same meanings as in the foregoing). Among the pyridazine derivatives (1), compounds (la), (lb), (lc), (Id), (le), (if), (ig), (lh), (li) System of law. (1) Production of the compound (la) in which the 4-position and 5-position are double bonds in which 'R is a low oxo group in the general formula (1): The compound (3) obtained by using the ester compound (2) will be borrowed As the compound (5) represented by R3_Y (R3 table has the same meaning as the preamble, γ represents a pixel atom or an esterified hydroxyl group), the compound (la) can be obtained by reacting in the presence of a base in a solvent. The compound (2) used here can be produced, for example, by the method described in Japanese Patent Application Laid-Open No. 7-69894. In addition, as the reactive ester group of the hydroxyl group, tosylsulfonyloxy group and methanesulfonyloxybenzenesulfonyloxy group are preferred. Compounds having these groups are made of pyridine, triethylamine, trimethylpyridine, and the like. In the presence of a base, it is obtained by reacting p-toluenesulfonyl chloride, methanesulfonyl chloride, anhydrous methanesulfonic acid, benzenesulfonyl chloride and the like with a hydroxyl compound. The reaction is completed in 1-5 to 50 hours at -15 to 50 t, and preferably to ⑺ ⑺ to ⑺ hours. As a solvent, pyridine, tetrahydrofuran, ether, ethyl acetate, dichloromethane, chloroform, N, N-dimethylformamide, dimethyl sulfoxide and the like. As the base used in the reaction between compound (3) and compound (5), inorganic bases such as potassium carbonate and sodium carbonate, pyridine, triethylamine, and diazabicyclo [5.4.0] 11 _7_ 晞 (DBU), etc. As the solvent, you can use nn · II-13- Standards for this paper (CNS) 1241295 A7 --__________ B7 V. Description of the invention (10) Methylformamide, dimethylmethylene, acetone, formazan Ethyl ketone, chloroform, dichloromethane, toluene, benzene and the like. The reaction ranges from 20 to 150. 〇 Under 丨 ~ add hours, preferably at 50 ~ 130 ° C to end in 2 to 10 hours. Furthermore, in compound (la), those in which R3 is amine phenylalkyl can be obtained by reducing the nitro group of the compound in which compound R3 is nitrophenylalkyl. In addition, by using this N-fluorenyl group The compound R3 is N-amidinophenylalkyl. (2) In the general formula (1), 'r4 is a carbamoyl group optionally substituted, and the compound (lb) at the 4-position and the $ -position is a double bond: By compound (3) in a solvent, and Compound (4) is obtained by reacting an amine represented by R6R7NH2 (R6 & R7 table has the same meaning as in the foregoing description), and using this as a raw material, compound (lb) can be obtained as in the reaction of compound (3) and compound (5). For the reaction of the compound (3) with an amine, for the compound (3), the amine is used in an amount of ˜3 to 30 equivalents, especially 疋 2 to 15 equivalents. As the solvent, methanol, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide and the like can be used. The reaction is performed at a temperature of from 10 to 200 ° C. for 5 to 24 hours, and preferably from 20 to 15 °. (: The end of the next 0.5 to 3 hours. The reaction of the compound (4) and the compound (5) ends in 20 to 15 (1 to 20 hours at TC, preferably 2 to 10 hours at 50 to 130 ° C) In addition, in the compound (lb), R3 is an aralkylamine formamidine group or a hydroxyalkylamine formamidine: fe group, and the aralkylamine or hydroxyalkylamine and R3 can be alkoxycarbonylalkyl groups. It can be obtained by the reaction of the compound. Also using the compound (la) as a raw material, the compound (lb) can be obtained in the same manner as the reaction from (3) and (4). (3) In the general formula (1), R 4 For the case of a substituted carbamoyl group, the compound (li) at the 4 and 5 positions is a single bond: -14-This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7

Intensive practice is used to reduce the compound 〇b) to obtain the compound, corpse: hunting…, ethanol, ethyl acetate, etc., with Pd / C, Ni Ni Temple as the catalyst, at room temperature to under heating Add chlorine. " (4) The compound in which 'R4 is several groups' in the 4-position and the 5-position is a double bond (ic): Compound ㈣ can be decomposed by acidity or detection in a solvent to obtain compound (1 (〇. & As the acid, there can be mentioned hydrochloric acid, Wei, trifluoroacetic acid, etc. As the test, causticity, 'ability', barium hydroxide, etc. can be used. As a solvent, water and methanol, ethanol,: propanol, etc. can be used. , N, N_ ~ Methylamine and other mixed solvents. The reaction time is 10 minutes to 5 hours at 150C, preferably ⑼ to ^^ 3 minutes, and the last name is bundled. &Quot; (5) General formula (1) In the formula, R4 is a low-carbon alkoxycarbonylamino group having a substituent as the case may be, and a compound having a double bond at the 4-position and the 5-position (manufactured by 1). The compound (lc) is not dissolved in the solvent or in the presence of a base. The compound (ld) can be obtained by reacting with alcohol and diphenylphosphonium (DPPA) represented by R8OH (the R8 table has the same meaning as the previous description). As a solvent, benzene, toluene, etc. can be mentioned. As the test, diethylamine, etc. can be used. The reaction is completed at 0.5 ~ 24 hours at 50 ~ 50 ° C, preferably 1 ~ 8 hours at 80 ~ 120 ° C. (6) Formula (1) in ' R is as appropriate Manufacture of a low-carbon alkyl group and a low-alkoxycarbonyl-substituted amine group as a substituent, and a compound (le) having a double bond at the 4- and 5-positions: Compound (Id) is dissolved in a solvent in the presence of a base and r9- Y (r9 and γ tables have the same meaning as in the previous description). Compounds can be obtained by reaction (丨. Reaction-15- __ '____ This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295

The reaction can be carried out as described above for the compound (3) and the compound (5). ⑺ In the general formula (1), R4 is a compound (丨 f) in which the 4-position and 5-position of the amine group substituted with a low-carbon alkynyl group optionally have a double bond (丨 f): Use compound (le) according to usage In a solvent, it is hydrolyzed under acidic or experimental conditions to obtain compound 0f). At first glance, the acid may be sulfuric acid, and the test may be caustic soda, caustic soda, hydroxide lock, etc. As the solvent, a mixed solvent of water and methanol, ethanol, a foreign material, tetrahydrofuran, N, N-methylformamide and the like can be used. The reaction is from 0 to 8. 〇 minutes to μ hours, preferably 0.5 to 8 hours at 20 to 120 t. (8) In the general formula (1), a compound in which R4 is an amine group and a double bond at the 4- and 5-positions (manufactured in 1): Compound (Id) is used in a solvent according to customary usage, and water is added under acidic or alkaline conditions Decomposition, compound (lg) can be obtained. As the acid, hydrochloric acid, sulfuric acid, etc., and as the base, caustic alkali, caustic potassium, barium hydroxide, etc. can be used. As the solvent, water and methanol, ethanol, isopropanol, tetrahydrofuran, N can be used. , N · dimethylformamide and other mixed solvents. The reaction is performed at 0 ~ 18〇 for 10 minutes to 24 hours, which is better than: ~ 丨 Finished at ^ ~ ^. (9) General formula (1 ) Manufacture of compound (ih) in which R4 is amidino group, low-carbon sulfonamido group or optionally substituted ureido group at the 4 and 5 positions: ⑴ Compound (lg) in solvent In the presence of a base, it is reacted with a compound represented by Rucox * (RUcOhCKR11 represents a lower alkyl group, an aryl group or a lower alkyl group, and χ represents a halogen atom). Among the compounds (lh), R4 is 醯Amine-based compounds. As / cereal media, P Pyoto, Tetrahydroan, Nizaki, Ethyl Acetate, Chlorine-16-This paper is applicable to China Standard (CNS) A4 (210 X 297 mm) 1241295 A7 ___________ B7 V. Description of the invention (13) Imitation, toluene, benzene, etc. It is also possible to use ethyl acetate, chloroform, toluene, benzene and other mixed solvents with water. As the base, organic bases such as pyridine, triethylamine, DBU, etc., inorganic bases such as caustic soda, caustic potassium, potassium carbonate, sodium carbonate, etc. can be used. The reaction is performed at -15 to 100 C for 1 to 50 hours, preferably _5. It ends at 2 ~ 25 hours at ~ 50 ° C. (11) RuS〇2X or (rUsolc ^ r11 and X are the same meanings as in the above) The compound of 2 or more equivalents shown above is the same as that of compound (lg). The reaction in the solvent in the presence of a base yields a di-lower alkanesulfonyl amine compound, which is then decomposed by hydrolysis in a solvent under alkaline conditions to obtain the compound 4 of the compound (111). As a solvent that can be used for hydrolytic decomposition, a mixed solvent of water and methanol, ethanol, isopropanol, tetrahydrofuran, N, N-dimethylformamide, etc. can be used, and an organic test such as pibidium can be used as a base. , Caustic steel, caustic unloading, carbonic acid, sodium carbonate, etc. The reaction is -15 ~ 100 ° C 10 minutes to 10 hours, preferably 0 to 80. The time is 0.5 to 5 hours. (Lii) The compound represented by the R WCCKR11 table has the same meaning as the preamble) is reacted with the compound (lg) in a solvent, Among the compounds (lh), compounds having a ureido group in which R4 optionally has a substituent can be obtained. As a solvent, toluene, benzene, or the like can be used, and the reaction is performed at 20 to 150. It is preferably 0.5 to 30 hours, preferably 1 to 8 hours at 50 to 120 ° C. (ίο) In the general formula (1), the compound (ib) or compound (li) where r4 optionally has a thiocarbonyl group can be obtained by using compound (lb) or compound (1 丨) in which X is 0 atom. X is converted into S atom. For example, a compound of 0 atom (丨 ... in a solvent, Lawesson's reagent (2,4-bis (4-methoxyphenyl) ", hydrazone disulfide-2,4-diphosphorane-2,4- Disulfide) can be converted into s-atom by using thioketone. -17- This paper is suitable for paper towels (CNS) Α4Λ 格 (21C) X29 ^ jy 1241295 A7 B7 V. Description of the invention (

LaWesSonfs reagent is 0.5 ~ 3 equivalents with respect to compound (lb), especially 1 ~ ΐ · 5 equivalents, and reacts at 30 ~ 15 (under rc, add time, preferably 50 ~ 100 ° It ends at 5 to 15 hours at C. As a solvent, toluene, xylene, etc. can be used. (11) In the general formula (1), R4 is a carbamoyl group or a thiamidine group having a substituent at the 4-position and 5 Production of compound (1 丨) with a single bond: 'R4 in compound (lb) is a carbamoyl group or a thiamidine group with a substituent as appropriate in a solvent, and pd / c is used as a catalyst As a solvent, methanol, ethanol, isopropanol, tetrahydrofuran, acetomethyl acetate, etc. can be produced by adding hydrogen. The reaction is performed for 1 to 50 hours at 15.0 to 2000, preferably. At 50 ~ 12 (2 to 20 hours at TC is the hope. The intermediates and target compounds obtained in the reactions of Liji are subjected to organic chemistry and are usually purified by methods such as filtration, extraction, washing, drying, concentration, Recrystallization, various chromatography, etc. can be separated and purified. In addition, the intermediate can be used for subsequent reactions without special purification. In addition, it can also be obtained as a solvent of a reaction solvent, a recrystallization solvent, etc., especially a hydrate. The thus obtained pyridazine derivative (1) of the present invention or a salt thereof has excellent interleukin inhibition. The effects that -1 does not produce can be used as a preventive or therapeutic agent for diseases caused by interleukin-1 / 5, such as immune system diseases, inflammatory diseases, ischemic diseases, osteoporosis, and sepsis, especially Rheumatism, immunodeficiency syndrome, arthritis, inflammatory colitis, ischemic heart disease, ischemic brain disorder, ischemic nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus, arteriosclerosis, Badgerson's Disease, Alzheimer's disease, leukemia, etc., medicines or interleukin-lyS production inhibitors, etc. The medicine of the present invention is a pyridazine derivative (1) or a salt thereof which is previously described as effective- 18-

This paper size applies to China National Standard (CNS) A4 specifications (21 × 297 mm) 1241295 A7 B7

V. Description of the invention (15 points, as the form of administration for this, ... Thousands, Putian grade, Ketian Tongzhao Noble agent, granule, powder, syrup, etc. Oral administration or intravenous injection, intramuscular injection Agents, suppositories, inhalants, percutaneous absorbents, eye drops, nose drops, etc. are administered orally. When preparing such pharmaceutical compositions in various dosage forms, it is possible to use this active ingredient alone or to appropriately combine other It can be pharmaceutically acceptable with A, valvain < carriers, such as excipients, binders, extenders, disintegrating agents, surfactants, lubricants, dispersants, buffers, preservatives, flavoring agents, flavors, coatings Membrane two = agent, diluent, etc. "π The dosage of the medicine of the present invention varies depending on age, weight, symptoms, administration method and number of administrations, etc., usually for adults! 〇〇〇〇〜１〇〇 〇mg is 0.1 ~ 100 g, and it is better to administer it once or divided into several oral or non-oral administrations. Examples Next, the present invention will be described by way of examples, but the present invention is not limited to these. Example 1 Example 4 -Methoxycarbonyl-6- (4-methoxyphenyl) -2-methyl_2fluorene- Manufacture of pyridazine_3_ ketone: in 4 -methoxycarboxymethoxyphenyl) _2Η-pyridazin-3-one 260 mg (l.oo mormol) of N, N-monomethylformamide ( 5 ml) of the solution was added with 346 g (2.50 mmol) of acid and 284 mg (200 mmol) of methyl iodide, and the mixture was stirred at 60 ° C for 2 hours. The inorganic matter was filtered off, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel tube, chromatography (silica gel 20 g, ethyl acetate / hexane (2/1), and crystallized from chloroform / hexane. 233 g (85.0%) of the title compound was obtained as yellow needle crystals. 0 Melting point · 1 〇9.2 -10 9.5 1241295 A7 B7 V. Description of the invention (1H-NMR (CDC13) 5: 3.87 (3Η, s) , 3.92 (3H, s), 3.97 (3H, s), 6.99 (2Η, d, Bu 8.9 Hz), 7.75 (2H, d, J = 8.9 Ηζ) 5 8.23 (1Η, s). IR (KBr) cm'1: 1743, 1713, 1660, 1607, 1518, 1278, 1250, 1 141, 1120, 1 101, 839. Mass spectrum (m / z): 274 (M +). Example 2 2-ethyl Production of 4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3 · one: 4-methoxycarbonyl-6- (4-methoxyphenyl) -2Η-pyridine The oxazin-3-one and ethyl moth as raw materials were treated in the same manner as in Example 1 to obtain the title compound at a yield of 79.4%. Pale yellow needle-like crystals (chloroform-hexane). Melting point: 76.5-77.6 ° C 1H-NMR (CDC13) (5: 1.46 (3Η, t, J = 7.2 Ηζ), 3.87 (3Η5 s), 3.98 (3Η, s), 4.35 (2Η, q, J = 7.2 Hz), 6.99 (2Η, d, J = 8.9 Hz) 7.76 (2H, d, J = 8.9 Hz), 8.22 (1H, s). IRCKBOcnT1: 1749, 1721, 1712, 1661, 1599, 1519, 1272. Mass spectrum (m / z): 288 (M +). Example 3 Production of 2-cyanomethyl-4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 4-methoxycarbonyl-6- (4-methoxybenzene Group) -2H-pyridazin-3-one and bromoacetonitrile as raw materials, and treated in the same manner as in Example 1 to obtain the title compound with a yield of 77.4%. -20- This paper is in accordance with China National Standard (CNS) A4 (210X) (297 mm)

Hold

1241295 A7 ^ ______ B7 V. Description of the invention (17) Yellow prism (chloroform-hexane) Melting point: 128.0-129.8 ° C 1H-NMR (CDC13) 5: 3.88 (3Η, s), 4.00 (3H, s) , 5.15 (2Η, s), 7.01 (2Η5 d, J = 9.0 Ηζ), 7.78 (2Η, d, J = 9.0 Ηζ), 8.31 (1Η, s). IIUKBOcm · 1: 1721, 1669, 1608, 1520, 1313, 1276, 1251. Mass spectrum (m / z): 299 (M +). Example 4 Production of 4-methoxycarbonyl-6- (4-methoxyphenyl) -2-n-propyl-2H-pyridazin-3 · one: 4-methoxycarboxy-6- (4 · methyl Oxyphenyl) -2H-pyridol-3-one and bromopropane were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 78.3%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 104.8-105.8 ° C 1H-NMR (CDC13) 5: 1.00 (3Η, t, J = 7.4 Ηζ), 1.84-1 · 99 (2Η, m), 3.87 (3Η, s), 3.98 (3H, s), 4.26 (2H, t, J = 7.4 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.75 (2H, d, J = 8.9 Hz), 8.21 (1H, s). IR (KBr) cm_1: 1718, 1668, 1609, 1519, 1316, 1277, 1253, 1 187, 1021, 838, 797. Mass spectrum (m / z): 302 (M +). Example 5 Production of 2- (2-cyanoethyl) -4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: -21-___________—— = ~ — -This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1241295 V. Description of invention (18) A7 B7

Using 4-methoxycarbonyl-6- (4-methoxyphenyl) _2Η_pyridazin_3_one and 3-chloropropionitrile as raw materials, the same treatment as in Example 1 was performed to obtain the title compound in a yield of 78.9%. 〇Yellow prism (chloroform-hexane) Melting point 140.6-143. It: ^ -NMRCCDC ^) δ: 2.99 (2Η, t, Bu 6.7 Ηζ, 3.87 (3 (, s), 3.99 (3H , S), 4.56 (2Η5 t, J = 6.7 Ηζ), 7.00 (2Η, d, J = 9.0 Ηζ), 7.77 (2Η, d, J = 9.0 Ηζ), 8.28 (1Η, s ). IR (KBr) cm-1: 2246, 1717, 1664, 1520, 1275, 1250. Mass spectrum (m / z): 313 (M +). Example 6 2_ (2_cyanoethyl) -4-ethoxy Production of carbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one Using 1-bromo-2-chloroethane as a raw material, the title compound was treated in the same manner as in Example 1 with a yield of 88.8%. Yellow needle crystals (chloroform-hexane) Melting point: 97.2-97.7 ° C ^ -NMRCCDCls) ( 5: 1.43 (3Η, t, J = 7.3 Hz), 3.87 (3H, s), 3.97 (2H, t, J = 6.4 Hz), 4.45 (2H, q, J = 7.3 Hz), 4.61 (2Η, t, J = 6.4 Hz), 7.00 (2H, d, J = 8.9 Hz), 7.75 (2H, d, J = 8.9 Hz), 8.21 (1H, s) IR (KBr ) cm * 1: 1707, 1673, 1605, 1523, 1389, 1321, 1275, 1261, 1 184, 1 130, 1034, 842. -22- This paper size applies to China National Standard (CNS) A4 (210 x 297) (Mm)

Binding

1241295 A7 B7 V. Description of the invention (19) Mass spectrum (m / z) · 338 (M +), 336 (M +). Example 7 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2-vinyl-2H-pyridazin-3-one and 4-ethoxycarbonyl-2- (2-hydroxyethyl)- Production of 6- (4-methoxyphenyl) -2H-pyridazin-3-one: In 2- (2-chloroethyl) -4-ethoxycarbonyl-6- (4-methoxyphenyl)- Add 2 mg of K2C03 to 115 mg (0.83 mmol) of 2H-pyridazin-3-one in a solution of 140 mg (0.15 mmol) of N, N-dimethylformamidine (1 ml) and stir at 80 ° C. 2 hour. After the inorganic matter was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was treated with silica gel column chromatography (silica gel 5 g), and the part was dissolved with ethyl acetate / hexane (1/2) to give a yellow oil. This gave 34 mg (27.2%) of the title compound (4-ethoxycarbonyl-6- (4-methoxyphenyl) -2-ethenyl-2H-pyridazin-3-one). 1H-NMR (CDC13) 5 ·· 1 · 42 (3Η, t, J = 7.1Ηζ), 3.87 (3Η, s), 4.44 (2Η, q, J = 7.1 Hz), 5.10 (1H, d, Bu 8.5 Hz), 5.95 (1H, d, J = 8.5 Hz), 7.00 (2H, d, B = 8.8 Hz), 7.80 (2H, d, J = 8.8 Hz), 7.87 (1H, dd, J = 8.5, 15.6

Hz), 8.18 (1H, s). The fraction was then separated from chloroform / methanol (20/1) and the title compound (4-ethoxycarbonyl-2- (2-hydroxyethyl) -6- (4-methoxyphenyl) -2H-pyridine was obtained as yellow crystals. Hydrazine-3_one) 93 mg (70.4%). Yellow needle-like crystals (chloroform-hexane) Melting point: 104.6-105.4 ° C 1H-NMR (CDC13) (5: 1.41 (3Η, t, Bu 7.3 Hz), 2.75 (1Η, br), 3 · 86 (3Η, s), 4.11 (2Η, t, Bu 5.1 Hz), 4.44 (2Η, q, J = 7.3 Hz), 4.50 (2H, t, J = 5.1 Hz), -23- Paper size applies Chinese National Standard (CNS) A4 specification (210 x 297 cm) 1241295 A7 B7 V. Description of the invention (20) 6.99 (2H, d, Bu 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz) , 8_19 (1H, s). IR (KBr) cm · 1: 3426, 1717, 1706, 1655, 1596, 1520, 1389, 13 16, 1266, 1027, 83 1,795. Mass spectrum (m / z): 318 (M +). Example 8 Production of 6- (3-chloro-4-fluorophenyl) -2-cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-one: 6- (3-chloro 4-fluorophenyl) -4-ethoxycarbonyl-2H-pyridazin-3-one and cinnamyl bromide as raw materials, and treated in the same manner as in Example 1 to obtain the title compound in a yield of 59.3%. Pale yellow oil ^ -NMRCCDCls) 5: 1.43 (3Η, t, J = 7.3 Ηζ), 4.45 (2Η, q, J = 7.3 Ηζ), 5.04 (2Η, dd, 1.0, 1.6 Hz) , 6.44 (1Η, td, J = 6.6, 15.8 Hz), 6.77 (1Η, d, J = 15.8 Hz), 7.21-7 · 41 (7Η, m ), 7.90 (1H, dd, J = 2.3, 6.9 Hz), 8_17 (1H, s). IR (thin film km1: 1749, 1668, 1605, 1504, 1264, 1148, 1021, 968, 924, 753, 693. Example 9 4-ethoxycarbonyl-2-isopropyl-6_ (4-methoxyphenyl) ) _2H-pyridazine ·% ketone production: using 4-ethoxyfluorenyl-6 pneumomethoxyphenyl) _2H • pyridazine 3-ketone and 2-bromopropane as raw materials, the same treatment as in Example 1, The title compound was obtained in a yield of 86.7%. Light yellow needle-like (chloroform_hexane) -24-The paper size is suitable for wealth X 297 ^) 1241295 A.7 B7 V. Description of the invention (2i Melting point: 140.6-141.1 ° C 1H-NMR (CDC13) 5: 1.42 ( 3H, t, J = 7.1 Ηζ), 1.44 (6Η, d, J = 6.6 Hz), 3.87 (3Η, s), 4.44 (2H, q, J = 7.1 Hz), 5.39-5.54 (lH M), 6.99 (2Η5 d, J = 9.0 Hz), 7.77 (2H, d, Bu 9.0 Hz), 8.14 (1H, s).

IR (KBr) cm ": 1713, 1664, 1601, 1518, 1390, 1323, 1271, 1177, 1132, 1030, S29. Mass spectrum (m / z): 316 (M +). Example 1 0 Packing 4-ethoxy Production of carbonyl-2_isobutyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one:

Line with 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one 600 mg (2.19 mmol) N, N-dimethylformamidine (6 ml) To the solution, 605 mg (4.28 mmol) of K2C03 and 360 mg (2.63 mmol) of 1-bromo_2-methylpropane were added, and stirred at 80 ° C for 30 minutes. After the inorganic matter was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (silica gel 15 g, hexane / ethyl acetate (1/1) to obtain the title compound, 705 mg (97.5%). Light yellow needle-like crystals (chloroform-hexane) Melting point: 83.0-83.3 ° C ^ -NMRCCDCls) (5: 0.99 (6H, d, J = 6.8 Hz), 1.42 (3Η, t, J 2 7.1) Ηζ), 2.29-2 · 45 (1Η, m), 3.87 (3H, s), 4 · 11 (2Η, d, P7.3 Hz), 4.44 (2Η5 q, J = 7.1 Hz), 6 · 99 (2Η, d, J = 8.9 Hz), 7.75 (2H, d, J = 8.9 Hz), 8.17 (1H, s) ° 丨 _25_ This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 Mm) 1241295 A7 B7 V. Description of the invention (22) IR (KBr) cm · 1: 1717? 1709, 1665, 1599, 1518, 1388, 1333, 1271, 1177, 1159, 1113, 1019, 829. Mass spectrum (m / z) ·· 330 (M +). Example 1 1 6_ (3,4-dimethoxyphenyl) -2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one production: Using 6- (3,4-dimethoxyphenyl) -4-methoxycarbonyl_2H-pyridazin-3-one and 1-bromo-2-methylpropane as raw materials, the same procedure was performed as in Example 1 to obtain the title. Compound with a yield of 86.6%. Crystal (chloroform-hexane) Melting point: 104.2-105.5 ° C ^ -NMRCCDCls) 5: 1.00 (6Η, d, J-6.8 Ηζ), 2.29-2 · 45 (1Η, m), 3.94 (3Η, s), 3.98 (3H, s), 4.02 (3Η, s), 4.13 (2Η, d, J = 7.3 Hz), 6.94 (2H, d, J = 8.6 Hz), 7.33 (1H, dd, J = 2.2, 8.6 Hz), 7.38 (1H, d, J = 2.2 Hz), 8.23 (1Η, s). IR (KBr) cm · 1: 1710? 1665, 1522, 1429, 1423, 1297, 1248, 1228, 1177, 1112, 1026. Mass spectrum (m / z): 346 (M +). Example 1 2 6- (3-Fluoro-4-methoxyphenyl) -2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one: 6- (3-said-4 -Methoxyphenyl) -4-methoxyphenyl-2H-fluorenol-3-one and 1-bromo-2-methylpropane as raw materials, and treated in the same manner as in Example 1 to obtain the title compound. Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of invention (23) Yield 69.9%. Yellow needle-like crystals (chloroform-hexane) Melting point: 119.3-121.3 ° C 1H-NMR (CDC13) 5: 0.99 (6Η, d, J = 6.6 Ηζ), 2.37-2 · 44 (1Η, m ), 3_95 (3H, s), 3.98 (3H, s), 4.11 (2H5 d, J = 7.3Hz), 6.99-7.07 (lH, m), 7.47-7.53 (1H, m), 7.57-7 64 (1Η, m), 8_23 (1H, s). IR (KBr) cm'1: 1746, 1660, 1522, 1434, 1290, 1195, 1178, 1136, 1099, 1013. Example 1 Production of 3 6- (3-Ga-4-methoxyethenyl) -2-isobutyl-4_methoxythanyl-2H -11 Tatamine-3-fluorene: -4-methoxyphenyl) -4-methoxymethoxy-2Η-11 daphta-3- 酉 was used as the starting material with 1-bromo-2-methylpropane, and treated in the same manner as in Example 1 to obtain the title compound The yield is 79.5%. Yellow needle-like crystals (chloroform-hexane) Melting point: 108.2-109.4 ° C ^ -NMRCCDCls) 5: 0 · 99 (6Η, d, J 6.6 Ηζ), 2.29-2.45 (1Η, m), 3.97 ( 3H, s), 3.98 (3H, s), 4.12 (2H, d, J = 7.3 Hz), 7.01 (1Η, d, J = 8.8 Hz), 7.67 (1H, dd, J = 2.2, 8.8 Hz ), 7.86 (1H, d, J = 2.2 Hz), 8.19 (1H, s). IRCKBOcnT1: 1713, 1663, 1603, 1 510, 1293. Mass spectrum (m / z): 352 (M +), 350 (M +). -27- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 ______ B7 V. Description of the invention (24) — ~~ 一 ^ Example 1 4 2-Isobutyl-4- Production of Methoxy-6- [4- (methylthio) phenyl] -2H-kinazin-3-one: As 4-methoxycarbonyl-6- [4- (methylthio) phenyl] -211-pyridol-3-one and 1-bromo-2-methylpropane were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 77.3%. Yellow needle-like crystals (chloroform-hexyl) Melting point: 90.4-91.4 ° C 1H-NMR (CDC13) 5: 0.99 (6Η, d, J = 6.6 Ηζ), 2.29-2 · 42 (1Η, m), 2.53 (3H, s), 3.98 (3H, s) 5 4 · 12 (2Η, d, J = 7.3 Hz), 7.32 (2H, d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz ), 8 · 23 (1Η, s).

Ii ^ KBiOcm · 1: 1714, 1672, 1601, 1502, 1268, 1251. Mass spectrum (m / z): 332 (M +). Example 1 5 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2- (3-methyl-2-butynyl) -2H-pyridazine_3_ Manufactured by: Ethoxycarbonyl_6_ (enmethoxymethoxyphenyl) -2Η-pyridazin_3_one and 丨 -bromo ·% methyl_2_butene were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield 87.6% 〇 Oil 1H-NMR (CDC13) δ · 1.42 (3H, t, J = 7.1 Ηζ), 1.75 (3Η, s), 1.86 (3Η, s), 3.86 (3Η, s), 4.44 (2Η, q, Hz), 4.87 (2Η, d, J 2 7.1 Hz), 5.43 · 52 · 52 (1Η, -28- This paper size applies to China National Standard (CNS) A4 Specifications (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (25) m), 6.99 (2Η, d, J = 8.9 Hz), 7.75 (2Η, d, J 2 8.9 Ηζ) , 8 · 16 (1Η, s) ° IR (KBr) cm · 1: 1745, 1713, 1668, 1609, 1519, 1309, 1260, 1181, 1 134, 1022, 835. Mass spectrum (m / z): 342 (M +). Example 1 6 Production of 2-cyclopropylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2Η · pyridazin-3-one: 4-ethoxycarbonyl-6- (4 -Methoxyphenyl) -2） -pyridazin-3-one and (cyclomethyl) cyclopropane as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 89.6%. Light yellow needle-like crystals (chloroform · Hexane) Melting point: 80.1-80.9 ° C 1H-NMR (CDC13) 5: 0.46--0.59 (4Η, m), 1.40-1.51 (4Η, m), 3.87 (3Η, s), 4.14 (2Η, d, J = 7.3 Hz), 4.44 (2Η5 q, J = 7.1 Hz), 6.99 (2Η, d, J = 9.0 Hz), 7.75 (2H, d, J = 9.0 Hz), 7.47-7.51 (2Η, m), 8.18 (1Η, s) 〇IR (KBr) cm · 1: 1715, 1706, 1664, 1598, 1389, 1273, 1128, 1114, 1020, 828. Mass spectrum (m / z): 328 (M +). Example 1 7 Production of 2-cyclopropylmethyl-6- (3,4-dimethoxyphenyl) -4-methoxycarbonyl_2-pyridazin-3_one: 6- (3,4- Dimethoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl) -29-This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 1241295 A7 B7 V. Description of the invention (26) Each propane was used as a raw material and treated in the same manner as in Example 1. The title compound was obtained in a yield of 78.7%. Yellow needle-like crystals (chloroform-hexane). Melting point: 136.5-137.3 ° C 1H.NMR ( CDC13) 5: 0.46--0.62 (4Η, m), 1.39-1.52 (1Η, m) 5 3.94 (3Η, s), 3.97 (3Η, s), 3.99 ( 3Η, s), 4.16 (2H, d, J = 7.3 Hz), 6.94 (1Η, d, J = 8.3 Hz), 7.33 (1H, dd, J = 2.2, 8.3 Hz), 7.39 (1H, d , J = 2.2 Hz), 8.23 (1H, s). IR (KBr) cm * 1: 1709? 1664, 1525, 1431, 1300, 1248, 1229, 1 176, 1 120, 1026, 1020. Mass spectrum (m / z): 344 (M +). Example 1 8 Production of 2-cyclopropylmethyl-6- (3-fluoro-4-methoxyphenyl) -4-methoxycarbonyl-2H-pyridazinone: 6- (3-fluoro-4 -Methoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl) cyclopropane as raw materials, and treated in the same manner as in Example 1 to obtain the title compound in a yield of 54.7%. Yellow needle-like crystals (chloroform-hexane) Melting point: 113.6-116.6 ° C lR ^ MR (COC \ 3) δ: 0.44_0_62 (4H, m), 1.37-1.52 (1H, m), 3.95 (3Η, s) 5 3 · 98 (3Η, s), 4.14 (2Η, d, J = 7.3 Ηζ), 7.00_7.07 (1Η, m), 7.48-7.53 (1Η m), 7.58-7 64 (1Η, m), 8.21 (1Η, s). -30- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (27 IR (KBr) cm'1: 1721, 1660, 1521, 1437, 1295, 1275 , 1258, 1106, 1023. Example 1 9 6- (3-fluoro-4-methoxyphenyl) -2 · cyclopropylmethyl-4-Toxycarbonyl-2H-pyridazin-3-one production: Using 6- (3-fluoro-4-methoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one and (chloromethyl) cyclopropane as raw materials, the same treatment as in Example 1 was performed to obtain the title. Compound, yield 72.7%. Pale yellow needle-like crystals (chloroform · hexane). Melting point: 101.4-103.8 ° C 1H-NMR (CDC13) 5: 0.45--0.62 (4 (, m), 1.48-1.52 ( 1H, m), 3.97 (3Η, s), 3.99 (3Η, s), 4.15 (2Η, d, J = 4.5 Hz), 7.01 (1Η, d, J = 8.5 Hz) , 7.66 (1Η, dd5 J = 2.4, 8.5 Hz), 7.87 (1Η, d, J = 2.4 Hz), 8.21 (1Η, s). IRCKBOcm · 1: 1718, 1660, 1602, 1509 , 1293. Mass spectrum (m / z): 350 (M +), 348 (M +). Example 2 0 2-Cyclopropylmethyl-4-methoxymethoxy-6- [4- (methylthio) phenyl Production of] -2H-pyridazin-3-one: 4-Hydroxycarbonyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3-one and Chloromethyl) cyclopropane as starting material, the same treatment as in Example 1, to give the title compound, a yield of 61.5% Yellow needles (chloroform-hexane)

Melting point: 100.2-101.8 ° C -31-This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 1241295 A7 B7 V. Description of the invention (28 ~~~~~ ^ -NMRCCDCls) 5: 0.41- 0.61 (4H, m), 1.38-1.51 (1H, m), 2.53 (3H, s), 3.98 (3Η, s), 4.15 (2Η, d, J = 7.3 Hz), 7.32 ( 2Η, d, J = 8.4 Hz), 7.73 (2H, d, J = 8.4 Hz), 8.2 (1H, s). n ^ KBOcnT1: 1713, 1668, 1602, 1328, 1267, 1249. Mass spectrum (m / z): 330 (M +). Example 2 1 Production of 2-cyclopentylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 4-ethoxyl-6- ( 4-Methoxyphenyl) -211_sulfuran-3-one and cyclopentylmethyl mesylate were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 88.5%. Light-colored needle-like crystals (chloroform · hex) Melting point: 63.6-64.4 ° C ^ -NMRCCDCls) 5: 1.26-1 · 46 (5Η, m), 1.49-1 · 81 (6Η, m), 2.50-2.66 (1H, m), 3.87 (3H, s), 4.23 (2Η, d, J = 7.6 Hz), 4.44 (2H, q, J = 7.1 Hz), 6.99 (2H, d, J = 8.8 Hz), 7.75 (2Η, d, J = 8.8 Hz), 8.17 (1H, s). IR (KBr) cm · 1: 1708? 1667, 1601, 1 5 1 8, 13 88, 1272, 1178, 1 130, 1 1 14, 1027, 827, 794. Mass spectrum (m / z): 356 (M +). Example 2 Production of 2 2-benzyl-4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 4-methoxycarbonyl-6- (4-methyl Oxyphenyl) -2H-pyridazin-3-one and benzyl bromide are original -32- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295

AT _____________ B7 V. Description of the invention (29) The title compound was treated in the same manner as in Example 1 with a yield of 96.9%. Pale yellow crystal ^ -NMRCCDCls) (5: 3.86 (3Η, s), 3.96 (3Η, s), 5.43 (2Η, s), 6.98 (2Η, d, J 2 9.1 Ηζ) , 7.28-7 · 37 (3Η, m), 7.47-7 · 55 (2Η, m), 7.75 (2Η, d, Bu 9.1 Ηζ), 8.22 (1Η, s), Mass spectrum (m / z): 350 (M +). Example 2 3 Production of 2-fluorenyl-4-ethoxycarbonyl-6- (4-methoxyphenylbuthazine-sulzine-3-one: 4-ethyl Oxycarbonyl-6- (4-methoxyphenyl pH-pyridazin-3-one and benzyl bromide as raw materials were treated in the same manner as in Example A to obtain the title compound in a yield of 7 $ 3%. Pale yellow crystal ln ^ MR (COC \ 3) δ: 1.41 (3Η, t, Bu 7.1 Ηζ), 3.86 (3Η, s), 4.42 (2Η5 q, J = 7.i Ηζ), 5.43 ( 2Η, s), 6.98 (2Η, d, J = 9.0 Ηζ), 7.26-7.36 (3Η, m), 7.50-7 · 55 (2Η, m), 7.75 (2Η, d, J: 9 .〇Ηζ), 8.17 (1Η, s). Example 2 4 2- (2, .4-Dichlorofluorenyl) -4-ethoxycarbonyl-6_ (cardiomethoxyphenyl) _2H_pyridazine Production of _3_ ketone: 4-ethoxycarbonyl-6- (4-methoxyphenyl) _2H_pyridazin-3_g is the same as 2, 'dichloromethyl chloride, and treated in the same manner as in Example 1' The title compound was obtained in a yield of 88.3%. (Chloroform - hexane)

Melting point: 135.7-136.3 ° C -33- The paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) 1241295 A7 B7 V. Description of the invention (3〇) lU ^ MR (COC \ 3) δ: 1.42 (3H, t, J = 7.1 Ηζ), 3.86 (3Η, s), 4_44 (2H, q, J = 7.1 Ηζ), 5.54 (2Η, s), 6.98 (2Η, d, J = 8.9 Hz), 7.20 (1Η, dd, J 2.2, 8.3 Hz), 7.29 (1Η, d, J = 8.3 Hz), 7.43 (1Η, d, J = 2.2 Hz), 7 71 (2Η, d5 J = 8.9 Hz), 8.22 (1Η, s). IR (KBr) cm · 1: 1748, 17 19, 1664, 160 8, 1 5 1 8, 13 11, 1254, 1242, 1 163, 1 136, 1026, 836. Mass spectrum (m / z): 436 (M +), 434 (M +), 432 (M +). Example 2 5 4-Methoxycarbonyl-6- (4-methoxyphenyl) -2- (4-nitrophenyl) · 2Η-pyridazin-3-one Production: 4_methoxycarbonyl-6 -(4-methoxyphenyl) · 2Η_pyridazin_3 · one and 4-nitropyridyl chloride as raw materials, and treated in the same manner as in Example 1 to obtain the title compound in a yield of 92.6%. Yellow fine needle-like crystals ( (Chloroform-Kiyuan) Melting point: 215.4-216.6 ° C ^ -NMRCCDCls) δ: 3.87 (3Η, s), 3.97 (3Η, s), 5.50 (2H, s) 5 7.00 (2H, d, J = 9.0 Hz) 5 7.67 (2H5 d5 J-8.8 Hz)? 7.74 (2H? D? J = 9.0 Hz) 9 8.20 (2H5 d, J = 8_8 Hz), 8.26 (1Η, s) o IRCKBOcm · 1 : 1720, 1663, 1601, 1552, 1347, 1255. Mass spectrum (m / z): 395 (M +). Example 2 6 Preparation of 2- (4-aminobenzyl) -4-methoxycarbonyl-6- (4-fluorenylphenyl) -2H-pyridazin-3-one-34- This paper is applicable to China Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (31 products: 4-methoxycarbonyl-6- (4-methoxyphenyl) · 2- (4-nitrobenzyl) ) To a solution of 100 mg (0.25 mmol) of -2H-sputum-3-one in methanol (30 liters) was added 10 / 〇pd / c 40¾ g, and contact reduction was performed at normal temperature and pressure. 3 〇 After the separation, the catalyst was filtered off, and the methanol was distilled off under reduced pressure. The obtained residue was crystallized from chloroform_ether_hexane, and fine needle-like crystals were developed to obtain 91 mg (98.5%) of the title compound. Melting point: 160.0 -161.9 ° C 1H-NMR (CDC13) (5: 3.65 (2Η, br), 3.87 (3Η, s), 3.95 (3Η, s), 5.31 (2Η, s), 6.63 (2H, d5 J = 8.4 Hz), 6.98 (2Η, d, J = 8.8 Hz), 7.36 (2H, d5 J = 8.4 Hz), 7.75 (2Η, d, J = 8.8 Hz), 8.19 (1H, s). IR (KBr) cm · 1: 34175 333 1? 1741, 1646, 1611, 1595, 1517, 1286, 1256, 1 181. Mass spectrum (m / z): 365 (M +). Example 2 7 4 -methoxycarbonyl-6- (4-methoxyphenyl) -2- [4- (3-p Production of Amine) Ethyl] -2H-pyridazin-3-one: In a suspension of 38 mg (0.31 mmol) of nicotinic acid in tetrahydrofuran (2 ml), add N- [3- ( Dimethylamino) propyl] -N, ethylcarbodiimide hydrochloride (WSC · HC1) 60 mg (0.31 mmol), stir off 5 minutes. Then 'Add 2- (4-amine ) -4 · methoxymethoxy-6- (4-methoxyphenyl) -2H-pyridazin-3_one 76 mg (0.21 mmol) solution in tetrahydrofuran (2 ml), at this temperature, Stir for 1 3 hours. Distill off the solvent under reduced pressure, and dissolve the residue in 30 ml of chloroform, then wash in the order of water (30 ml) and saturated brine (30 t liters), -35-paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 __B7 V. Description of the invention (32) ~~~ * One _ ~~~~~ Drying with anhydrous NaJO4. Distilling off the solvent residue under reduced pressure The material was separated and purified by silica gel chromatography (developing solvent: chloroform / methanol (1/10/1), and then purified from chloroform-hexane & . Melting point: 235.7-236.9. 〇 (decomposition) 1H ^ NMR (CDC13) 5: 3.87 (3H, s), 3.92 (3H, s), 5.42 (2H, s), 7.0 (2Η, d, J = 9.0 Hz), 7.40 -7 · 46 (1Η, m), 7.56 (2Η, d, J = 8.5 Hz), 7.63 (2Η, d, J = 8.5 Hz), 7.76 (2Η, d, J = 9.0 Hz ), 8.07 (1Η, br), 8.19-8.25 (2H, m), 8.75-8.78 (1H, m) 5 9.88-9 · 12 (1Η, s). IR (KBr) cm · 1: 3303? 3266, 1740? 1668, 1640, 1606, 1542, 1518, 1412, 1321, 1253. Mass spectrum (m / z): 470 (M +). Example 2 Production of 8 4-methoxycarbonyl-6- (4-methoxyphenyl) -2- (3-pyridylmethyl) -2H-pyridazin-3-one: 4-methoxycarbonyl-6 -(4-methoxyphenyl) -2H-pyridazin-3-one and 3- (chloromethyl) pyridine hydrochloride were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 38.5%. Light yellow needle-like crystals (chloroform-ether-hexane) Alkane point: 112.3-115.3 ° C (decomposition) 1H-NMR (CDC13) 5: 3.87 (3Η, s), 3.97 (3H, s), 5. · 44 (2Η, s), 6.99 (2Η, d, M.0 Ηζ), 7.24-7.30 (1Η, m), 7.74 (2Η, d, J = 9.0 = ζ), 7.86-7.92 (1Η, m), 8.24 (1Η, s), 8.54-8.57 (1Η, m), 7.98 · 8.81 (1Η, m). -36- This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1241295 A7 B7 V. Description of the invention (33) IR (KBr) cm_1 ·· 1720, 1665, 1599, 1518, 1311, 1270. Mass spectrum (m / z): 351 (M +). Example 2 9 4 · Methanyl-6- (4-methoxyphenyl) -2- (3-phenylpropyl) -2H-pyridazin-3-one production: 4-methoxyfluorenyl -6- (4-methoxyphenyl) -2H-pyrazin-3-one and 3-phenylpropyl bromide were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 94.0%. Yellow oil lU ^ MR (COC \ 3) δ: 1.42 (3Η, t, J = 7.1 Ηζ), 2.17-2.30 (2H, m) 5 2.74 (2H, t, J = 7.8 Hz), 3 86 (3Η, s), 4.33 (2Η, t, J = 7.1 Hz), 4.44 (2Η, q, J = 7.1 Hz), 6.98 (2H, d, J = 8.9 Hz), 7.13- 7.30 (5H, m), 7.74 (2H, d, 8.9 Hz), 8.14 (1Η, s), IR (thin film km-1: 1744, 1713, 1664, 1610, 1519, 1256, 1180, 1131, 1021. Mass spectrum (m / z): 392 (M +). HRMS: Calculated (found) C23H24N2 04: 392 17358 (392 171〇7) Example 3 0 2-Cinnamyl-4-ethoxycarbonyl-6 Manufacture of-(4-methoxyphenyl) -2H-pyridazin-3-one: 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one and cinnamyl Bromine was used as a raw material, and treated in the same manner as in Example 1. The title compound was obtained in a yield of 92 ·%. Pale yellow needles-37- This paper is in accordance with China National Standard (CNS) A4 (21 × 297 mm) 1241295 A7 B7 V. Explanation of the invention (34) ^-NMRCCDCls) 5: 1.42 (3Η, t, J = 7.1 Ηζ), 3.86 (3Η, s), 4.45 (2H, q, J = 7-1 Hz), 5.03 (2Η, d, J = 6.6 Hz), 6.46 (1Η, td, J = 6.6, 15.9 Hz), 6.75 (1H d, J two 15.9 Hz), 6.99 (2H, d, J = 9.0 Hz), 7.20-7.41 (5H, m), 7.76 (2H, d, J = 9.0 Hz), 8.19 (1H5 s). IR (thin film km · 1: 1744, 1713, 1668, 1609, 1518, 1309, 1256, 1025, 835. Example 3 1 2- (4-chlorocinnamyl) -4-ethoxycarbonyl-6- (4- Production of methoxyphenyl) -2H-pyridazin-3-one: 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one and 4-chlorocinnamyl chloride As the starting material, the title compound was treated in the same manner as in Example 1. The yield was 85.7%. Yellow needle-like crystals (chloroform-hexane). Melting point: 127.0-127.9 ° C 1H-NMR (CDC13) 5: 1.42 (3Η) , T, J = 7.1 Ηζ), 3.87 (3Η, s), 4.45 (2Η, q, J = 7.1 Hz), 5.02 (2H, td, J = 1.0, 6.6 Hz), 6.42 (1H, td, J = 6.6, 15.9 Hz), 6.69 (1Η, td, J = 1.0, 15.9 Hz), 6.99 (2Η, d, J = 8.9 Hz), 7.26 (2H, d, J = 8.9 Hz ), 7.32 (2H, d, J = 8.9 Hz), 7.76 (2H, d, J = 8.9 Hz), 8_20 (1H, s). IR (KBr) cm · 1: 1705, 1662, 1601, 1520, 1492 , 1388, 1309, 1263, 1181, 1149, 1026, 1015, 831. Mass spectrum (m / z): 426 (M +), 424 (M +). -38- This paper size applies to China National Standard (CNS) A4 specifications ( 210x 297 mm) 1241295 A7 ____________ B7 i, & Instructions (35) — ~~~ ~~ ~~ Implementation Example 3 Production of 2 2- (4-chlorocinnamyl) -6- (3,4-dimethoxyphenyl) _4-methoxycarbonyl-211-pyridazin_3_ ketone: 6- (3,4 · Dimethoxyphenyl) -4-methoxycarbonyl-211-¾¾azin-3-one and 4-chlorocinnamyl chloride as raw materials, and treated in the same manner as in Example 1 to obtain the title compound in a yield of 77.7%. Crystal (chloroform-hexane) Melting point: 117.5-118.7 ° C 1H-NMR (CDC13) 5: 3.94 (3Η, s), 3.95 (3Η, s), 3.99 (3Η, s), 5 · 03 (2Η, dd, J = 1.0, 6.6 Hz), 6.43 (1H, td, J = 6.6, 15.9 Hz), 6.70 (1H, td, J = 1.0, 15.9 Hz), 6.94 (1H, d, J = 8.3 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.33 (1Η, dd, J = 2.2, 8.3 Hz) , 7.38 (1H, d, J = 2.2 Hz), 8.26 (1H, s). IR (KBr) cm i: 3046, 1704, 1674, 1516, 1419, 1247, 1226, " 51, 1023, 979. Mass spectrum (m / z): 442 (M +), 440 (M +). Example 3 Production of 3 2-(4-chlorocinnamyl) -6- (3-fluoro-4-methoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one ·· 6- (3-Fluoro-4-fluorenylphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorocinnamyl chloride were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield 75.5%. Light yellow needle-like crystals (chloroform-hexane) -39- This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 1241295 A7 B7 _______ Description ~~-" Melting point: 131.3-132.3 ° C lU ^ MR (COC \ 3) δ: 3.95 (3Η, s), 3.99 (3Η, s), 5.02 (2Η, dd, J ^ ll, 6.7 Ηζ), 6.42 (1Η, td, J 6.7, 15.9 Ηζ), 6.70 (1Η, td5 J = 11, 15.9 Ηζ), 7.00 · 07 · 07 (1Η, m), 7.28 (2Η, d, J 8.9 Ηζ), 7.31 (2Η5 d, J 2: 8.9Ηζ), 7.48-7.53 (1Η, m), 7.59-7 · 66 (1Η, m), and 8.22 (1Η5 s). IRCKBiOcnT1: 1725, 1661, 1654, 1523, 1319, 1271, 1129. Mass spectrum (m / z): 430 (M +), 428 (M +). Example 3 Production of 4 2- (4-chlorocinnamyl) -6- (3-chloro-4-methoxyphenyl) -4-methoxycarbonyl-2pyridazin-3-one: 6- ( 3-Chloro-4 -methoxyphenyl) -4 -methoxythio-2H-pyridone-3 · one and 4-chlorocinnamyl chloride as raw materials, treated in the same manner as in Example 1 to obtain the title compound in a yield 76.8%. Yellow prisms (chloroform-hexane) Melting point: 179.7-181.6 ° C ^ -NMRiCDCls) 5: 3.97 (3H, s), 3.99 (3Η, s), 5.02 (2H, dd5 J = 11, 6.7 Hz), 6.42 (1H, td5 J-6.7, 15.9 Hz), 6.71 (1H, td, J = ll, 15.9 Hz), 7.01 (1H, d, J = 8.6 Hz), 7.28 (2H, d5 J = 8.8 Hz), 7.31 (2Η, d, J = 8.8 Hz), 7.66 (1H, dd, J = 2.2, 8.6 Hz), 7.88 (1H, d, J = 2.2 Hz), 8.22 (1H, s). IRCKBOcnT1: 1747, 1652, 1605, 1508, 1286, 1260, 1240. Mass spectrum (m / z): 446 (M +), 444 (M +). -40- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 Five-factory ~ —————— " Example 3 5 2- (4-chlorocinnamyl)- Production of 4-methoxycarbonyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3_one: 4-methoxycarbonyl-6- [4- (methylthio) phenyl] -2H_pyridazin-3-one and 4-chlorocinnamyl chloride as raw materials were treated in the same manner as in Example 1 to obtain the title compound in a yield of 82.3%. Yellow prism (chloroform-Tiger) Melting point: 123.3-126.2 ° C ^ -NM ^ CDCls) 5: 2.53 (3Η, s), 3.98 (3Η, s), 5.03 (2Η, dd, J = ll, 6.7 Hz), 6.43 (1H, td, J = 6.7, 15 · 9 Hz), 6.70 (1Η, td, J = ll, 15.9 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz), 8.26 (1 ·, s). IR (KBr) cm · 1: 1712, 1666, 1600, 1502, 1490, 1270, 1095, 977 ° Mass spectrum (m / z): 428 (M +), 426 (M +). Example 3 6 2- (2,4-Difluorocinnamyl) -4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one Production: 4-ethoxy Carbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one and 2,4-difluorocinnamyl chloride were used as raw materials and treated in the same manner as in Example 1 to obtain the title compound in a yield of 92.0%. 1H-NMR (CDC13) 5: -41-The size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 __ _ _ B7 V. Description of the invention (38) 1.42 ( 3H, t, J = 7.1 Ηζ), 3.87 (3Η, s), 4.45 (2H, q, J = 7.1 Hz), 5.04 (2Η, dd, J = 1.0, 6.6 Hz) , 6.48 (1Η, dd, J = 6.6, 16.0 Hz), 6.73-6.87 (3H, m), 6.99 (2Η, d, J-8.9 Hz), 7.37-7.47 (1H, m), 7.76 (2H, d, J = 8.9 Hz), 8.20 (1H, s). IR (film) cm-1: 3074, 1745, 1713, 1668, 1610, 1519, 1503, 1258, 1141, 1026, 967. Mass spectrum (m / z): 426 (M +). 11 «^ 18: Calculated value (measured value) <: 23112 (^ 21 ^ 2〇4: 426.13908 (426.14058). Example 3 7 4-methoxycarbonyl-6- (4-methoxyphenyl) -2 -[4 · (methylthio) phenylamine formamidinemethyl] -2Η-pyridazin-3-one production: (1) Production of 2-bromo_4f- (methylthio) acetonitrile: at 4- (Methylthio) aniline 200 mg (1.44 mmol) in 2 ml of chloroform solution 2 ml of a saturated NaHCCh aqueous solution, and under cooling with ice water, 300 g of bromoacetic acid bromide (1.49 mmol) was added in 2 ml And stirred at room temperature for j hours. The chloroform layer was separated, washed in the order of 2N HC1 (10 ml), saturated brine (10 ml), and dried over anhydrous Na2S04. The solvent was removed under reduced pressure, and the brown Crystallization gave 356 mg (95.3%) of the title compound. 2) 4-methoxycarbonyl-6- (4-methoxyphenyl) _2_ [cardio (methylthio) phenylaminomethanemethyl] -2H-pyridazine Production of -3-one: Based on 4-methoxy phenyl (4_methoxyphenyl) _2H_pyridine_3, and 2_mo_4, _ (methylthio) ethyl aniline as raw materials, Treated in the same way as the implementers, a titled character was obtained with a yield of 90.0%. Mouth yellow prisms (chloroform-hexane) -42-1241295 A7 ________________ B July description (3: ~ 7 ~~~ '— Melting point: 130.2-132.4 ° c lH-NMR (CDCl3) 5: 2.44 (3H, s) , 3.87 (3H, s) 5 3.98 (3Η, s), 5.08 (2Η, s), 6.98 (2H, d, Bu 8.9 Hz), 7.19 (2Η, d, J = 8.7 Hz) , 7.46 (2H, d, J = 8.7 Hz), 7.78 (2Η, d, J = 8.9 Hz), 8.32 (1H, s) 5 8.64 (1H, br). IRCKBOcnT1: 3273, 1744, 1702, 1652 , 1598, 1518, 1250. Mass spectrum (m / z): 439 (M +). Example 3 8 2 · Benzyl-4-aminomethylmethyl-6 · (4-methoxyphenyl) -2H-pyridazine Production of 3-one: Add ammonia to 2-benzyl-4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one 73 mg (0.20 mmol) 3 ml of a methanol solution (about 10% W / W) was stirred at room temperature for 17 hours. The precipitated crystals were collected by filtration and the title compound was obtained as colorless fine needle crystals (59 mg (90.7%)). Melting point: 196.0-198.0 ° C ^ -NMRCCDCls) 5: 3.87 (3Η, s), 5.48 (2H, s), 5.93 (1Η, brs) 5 6 · 99 (2Η, d, Bu 9 · 0 Hz), 7. · 30-7 · 40 (3Η, m), 7.49 (2H, dd, J = 2.0, 8.1 Hz), 7.83 (2H, d, J = 9.0 Hz), 8.67 (1Η, s), 9.4 1 (1H, b0. IRCKBOcnT1: 3 157, 1703, 15 18, 1391, 1255, 1034, 830, 729. Example 3 9 4-Aminomethylamido-2-cyclopropylmethyl-6- (4- Production of methoxyphenyl) -2H-pyridazin-3-one: 2-cyclopropylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one As the raw material, the same treatment as in Example 3 and 8 was carried out to obtain the title compound. Yield -43- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (4 (3 90.5%. Pale yellow prisms (methanol-ether) Melting point: 182.2-183.3 ° C ^ -NMRCCDCls) 5: 0.47-0 · 62 (4Η, m), 1.40-1 · 51 (1Η, m) , 3.87 (3H, s), 4.19 (2H, d, J = 7.3 Hz), 5.95 (1H, br), 7.00 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J = 8 · 8 H z), 8 · 6 8 (1H, s), 9.50 (1PJ, br) 0 IR (KBr) cm_1: 3322, 3161, 1694, 1610, 1519, 1419, 1386, 1269, 1252, 1 184, 1024 , 839. Mass spectrum (m / z): 299 (M +). Example 4 Manufacture of 4-aminomethylmethyl-2-cyclopentylmethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-cyclopentylmethyl-4- Ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 38 to obtain the title compound in a yield of 91.5%. Colorless needle-like crystals (chloroform-hexane) Melting point: 182.2-183.3 ° C lU ^ UR (COC \ 3) δ · 1.31-1 · 46 (2Η, m), 1 · 50-1 · 83 (6Η, m) , 2.48-2 · 65 (1Η, m), 3.87 (3Η, s), 4.28 (2Η, d, J = 7.6 Ηζ), 5.94 (1 (, br), 7.00 (2Η, d, J = 8.9 Ηζ), 7.82 (2Η, d, J = 8.9 Ηζ), 8.67 (1Η, s), 9.51 (1Η, br) ο IR (KBr) cm " 1: 3350, 3 158, 1701v 1517, 1457, 1389, 1254, -44- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1241295 A7 _____B7 V. Description of the invention (41) 1189, 1177, 1131, 1033, 828, 799. Mass spectrum (m / z): 327 (M +). Example 4 1 Production of 4-aminomethylamidino-2-cinnyl-6- (4-methoxyphenyl) · 2fluoren-pyridazin-3_one: 2-Cinnamyl-4-ethoxycarbonyl -6- (4-methoxyphenyl) -2'-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 38 to obtain the title compound in a yield of 40.0%. Colorless fine needle-like crystals (chloroform-ether) Melting point: 184.0-186.0 ° C ^ -NMRCCDCls) 5: 3.87 (3Η, s), 5.08 (2Η, dd, J = 1.6, 6 · 6 Hz ), 5.93 (1Η, brs), 6.44 (1Η, td, J = 6.6, 15.9 Hz), 6.75 (1H, td5 J = 1.0, 15.9 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.24-7.43 (5H, m), 7.83 (2H, d5 J = 9.0 Hz), 8.69 (1Η, s), 9.44 (1H, br). IRCKBOcnT1: 3347, 3148, 1704, 1633, 1610, 1517, 1391, 1254, 1034, 829. Example 4 Production of 2-Aminomethyl-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridol-3-one: 2- (4-chloro Cinnamyl) -4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 38 to obtain the title compound in a yield of 96.6%. Light yellow fine needle-like crystals (chloroform-hexane)

Melting point: 195.1-195.5 ° C 1h- ^ uk (coc \ 3) δ: -45- This paper size is applicable to China National Standard (CNS) A4 specification (210 x 297 mm) 1241295 A7 _______ ΒΊ V. Description of the invention (42 ) _ ^^ ~~ " " " — 3.87 (3H, s), 5.07 (2H, td, Bu 1.0, 6 · 6 Hz), 5.98 (1H, br), 6.42 (1H, td, J = 6.6, 15 · 8 Hz), 6.69 (1Η, td, J 1.0, 15.8 Hz), 6.99 (2Η, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.33 (2Η, d, J = 8.6 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.69 (1H, s), 9.43 (1H, br). IR (KBr) cm · 1: 3324, 3142, 1702, 1611, 1 570, 15 1 8, 1491, 1388, 1257, 1 169, 1034, 83 1. Mass spectrum (m / z): 397 (M +), 395 (M +). Example 4 3 Production of 2-isobutyl-6- (4-methoxyphenyl) -4-methylaminomethane-2H-pyridazin-3-one: 4- 4-ethoxycarbonyl · 2_ Isobutyl-6- (4-methoxyphenyl) -2H-pyridazin-3_one 40 mg (0.13 mmol) was added with 30% methylamine-ethanol solution (2 ml), and stirred at room temperature for 3 0 marks. The solvent was distilled off under reduced pressure, and the residue was crystallized from chloroform-hexane to obtain the title compound (35 mg, 91.9%) as colorless needles. Melting point: 124.9-125.2 ° C ^ -NMRCCDCls) 5: 1.00 (6Η, d, J = 6.6 Ηζ), 2.37-2 · 44 (1Η, m), 3.02 (3Η, d, J = 5.3 Hz), 3.87 (3H, s), 4.15 (2H, d, J = 7.3 Hz), 6.99 (2Η, d, J = 8.9 Hz), 7.82 (2Η, d, J = 8.9 Hz) , 8.67 (1H, s), 9.72 (1Η, br). IRCKBOcnT1: 3244, 1686, 1590, 1253, 1 183, 1026, 834. Mass spectrum (m / z): 315 (M +). Example 4 Manufacture of 6- (4-methoxyphenyl) -2-methyl-4-methylaminomethylmethyl-2H-pyridazin-3-one: -46- The paper size is applicable to Chinese national standards (CNS) A4 size (210 X 297 mm) 1241295 A7 __________ B7 V. Invention 43 y ~~ ~~~ ~ With 4-methoxycarbonyl-6- (4-methoxyphenyl) _2_methyl-2H -Pyridazine 3-ketone was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 95 3%. Slightly yellow needle-like crystals (chloroform-hexane) Melting point: 150.5-150.7 ° C 1U-1SIMR (COC13) δ: 3.03 (3H, d, J = 5_0 Ηζ), 3.87 (3Η, s), 3.95 (3H , S), 6.99 (2H, d, J = 8.9 Ηζ), 7.82 (2Η, d, J = 8.9 Ηζ), 8.68 (1Η, s), 9.67 (1Η, br). IR (KBr) cm · 1: 3248? 1679, 1625, 1610, 1517, 1459, 1284, 1249, 1 185, 1004, 838. Example 4 5 Production of 2-ethyl-6- (4-methoxyphenyl) -4-methylaminemethylmethyl-2H-pyridazin-3-one: 2-ethyl-4 -methoxy Carbonyl-6- (4-methoxyphenyl) -2H-pyridin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 82.8%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 122.4-122.9 ° C lH-NMR (CDCl3) (5 · 1.50 (3H, t,] = 7 · 3 Ηζ), 3 · 03 (3 (, d5 J = 5.0 Hz), 3.87 (3H, s) 5 4.38 (2H, q, J = 7.3 Hz), 7.00 (2H, d, J_8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.67 (1Η, s), 9.72 (1Η, br). IR (KBr) cm · 1: 3241, 1674, 1 567, 1553, 1 5 17, 14 15, 125 1, 1183, 1025. Mass spectrum (m / z): 287 (M +). Example 4 6 -47- This paper size applies Chinese National Standard (CNS) A4 (210x 297 mm) 1241295 A7 ___________________ B7 Five γ Description of the invention (44 y ~~~~~~ ~~~~ — Manufacture of 2-cyanomethyl-6_ (4-methoxyphenyl) -4 -methylamine methylamido-2Η- ^ 嗔 -3-one: 2-cyanomethyl-4- Methoxycarbonyl-6- (4 · methoxyphenyl) -2Η-pyridazin-3 · one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 8280/0. Pale brown prisms ( Chloroform-hexane) Melting point: 153.4-154.9 ° C 1H-NMR (CDC13) (5: 3.04 (3Η, t, J = 5.3 Hz), 3.88 (3H, s), 5.16 (2H, s), 7 · 01 (2Η, d, J = 8.9 Ηζ), 7.83 (2Η, d, J = 8.9 Hz), 8.74 (1H, s), 9.28 (1 Η, br). IRCKBOcnT1: 3292, 2261, 1690, 1679, 1554, 1517, 1257. Mass spectrum (m / z): 298 (M +). Example 4 7 6- (4-methoxyphenyl) -4- Production of methylaminomethyl-2-methylaminomethylmethyl-2H-pyridol-3-one: (1) 4-ethoxycarbonyl-2-ethoxycarbonylmethyl-6- (4- Production of methoxyphenyl) -2H-pyridol-3-one: 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2hydrazine-3-one and ethyl bromoacetate are implemented as Treatment of Example 1 gave the title compound in a yield of 84.5%. Pale yellow needle-like crystals (chloroform-hexane). Melting point: 77.1-77.8 ° C ^ -NMRCCDCls) 5: 1.29 (3Η, t, J = 7.1Ηζ ), 1.41 (3Η, t, Bu 7.1 Ηζ), 3.86 (3Η, s), 4.26 (2H, q, J = 7.1 Hz), 4.43 (2H, q, J = 7.1 Hz), 4.99 (2Η, s), 6.98 (2H, d, Bu 8.9 Hz), 7.73 (2H, d, J = 8.9 Hz), 8.25 (1H, s). -48- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (45 IR (KBr) cm · 1 1754, 1718, 1675, 1607, 1518, 1313, 1284, 1264, 1217, 1159, 1030, 1018, 842, 794. Mass spectrum (m / z): 360 (M +). (2) 6- (4-methoxyphenyl) -4-methylaminomethylmethyl Production of 2-methylamine formamidinemethyl-2H-pyridazin-3-one:

Using 4-ethoxycarbonyl-2-ethoxycarbonylmethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-hydrazone as the starting material, the same treatment as in Example 43 was carried out to obtain the title compound, Yield was 84.5%. The melting point of fine acicular crystals: 250.1-250.8 ° C ^ -NMRCCDCla) (5: 2.87 (3Η, d, J = 4.6 Hz), 2.99 (3Η, d, J = 5.0 Hz), 3 87 (3Η, s), 4.95 (2Η, s), 6.14 (2H, br), 6.98 (2Η, d, J = 9.1 Hz), 7.82 (2Η, d, J = 9.1 Hz ), 8.70 (1Η, s), 9.44 (1H, br).

IR (KBr) cm · 1: 3293? 3 1 14, 1683, 1666, 1516, 1252, 1164, 1026, 834, 798. Mass spectrum (m / z): 330 (M +). Example 4 8 6- (4-Methoxyphenyl) -4-methylcarbamate-2-ethynyl-2H-fluoren-3-one production: 4-ethoxycarbonyl-6- (4-Methoxyphenyl) -2-vinyl-2H-sulmon-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 36.70 / 〇. Yellow needle-like crystals (chloroform-hexane)

Melting point: 130.3-132.8 ° C -49- The paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (46) 1H-NMR (CDC13) 5: 3.03 (3H , D, J = 5.0 Hz), 3.88 (3H, s), 5.18 (1Η, d, J = 8.6 Hz), 6.03 (1H, d, J = 15.4 Hz), 7.01 (2Η, d, J = 9.0 Hz), 7.85 (1H, dd, Bu 8.6, 15.4 Hz), 7.89 (2H, d, J = 9.0 Hz), 8.70 (1Η, s), 9.50 (1H, bo. IR (KBr ) cm-1: 3238, 3 121, 1683, 1632, 1607, 1548, 1516, 1411, 1314, 1272, 1245, 1180. Example 4 9 2- (2-hydroxyethyl) -6- (4 • A Oxyphenyl) -4 • methylamine methylamidino-2H-pyridazin-3-one production: 4- 4-ethoxycarbonyl-2- (2-hydroxyethyl) -6- (4-methoxyphenyl ) -2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 43 to obtain the title compound with a yield of 97.2%. Pale yellow needle-like crystals (chloroform-hexane). Melting point: 160.3-160.6 ° C Towel-NMR (CDC13) 5: 2.87 (1H, brt, J = 5.7 Hz), 3.00 (3H, d, J = 5.1 Hz), 3.87 (3H, s), 4.17-4 · 19 (2Η, m), 4.51 -4.56 (2Η, m), 7.00 (2Η, d, J = 8.9 Hz), 7.80 (2Η, d, J = 8.9 Hz), 8.69 (1H, s), 9 .57 (1H, br). IR (KBr) cm'1: 3462, 3228, 1671, 1619, 1592, 1536, 1519, 1265, 1 187, 1070, 833. Mass spectrum (m / z): 303 (M + ) Example 5 0 2- (2-Gasethyl) -6- (4-methoxyphenyl) -4-methylamine methylphenidate · 2Η -Made by Seki-3- 嘻: -50- paper Standards are applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 1241295 A7 B7 V. Description of the invention: 2- (2-cyanoethyl) -4-methoxycarbonyl_6_ (4_methoxyphenyl) -2] ^ pyridazine_3_one as a raw material, treated in the same manner as in Example 43 to obtain the title compound with a yield of 903%. Slightly yellow fine needle-like crystals (chloroform · hexane). Melting point · 164_5-167.2 (: (Decomposition) ^ -NMRCCDCls) ^: 2.99 (2Η, t, Bu 6_7 Ηζ), 3.03 (3Η, d5 Bu 5.0 Ηζ), 3.87 (3Η, s), 4.59 ( 2Η, t, Bu 6.9 Ηζ), 7.00 (2Η, d, Bu 8.6 Ηζ), 7.83 (2Η, d, J = 8.6 Ηζ), 8.71 (1Η, s), 9.44 (1Η , Br). IR (KBr) cm 1: 2246, 1717, 1664, 1520, 1275, 1250. Mass spectrum (m / z): 312 (M +). Example 5 1 6- (4-Methoxyphenyl) -4 · methylaminomethylmethyl-2-n-propyl-2H-pyridazin-3-one Production: 4-Methoxycarbonyl-6- (4-Methoxyphenyl) -2-n-propyl-2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 85.3%. Colorless needle-like crystals (chloroform-hexane). Melting point: 106.5-107.1 ° C ^ -NMRCCDCls) 5: 1.02 (3H, t, J = 7.3 Hz), 1.85-2.00 (2H, m), 3.02 (3Η, d, J = 5.0 Hz), 3.87 (3H, s), 4.29 (2H, t, J = 7.3 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.82 (2Η, d, J = 8.9 Hz), 8.66 (1H, s), 9.72 (1H, br). IRCKBOcnT1: 3266, 1690, 1549, 1517, 1248, 1 185, 1027. Mass spectrum (m / z): 301 (M +). Example 5 2 -51-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Binding

Line 1241295 A7 —B7 Description (48 ~~~~~~~ 2 -Xingpropyl-6- (4-methoxydongyl) -4-methylaminemethyl-2H -Seamazine_3_one Production: Using 4-ethoxycarbonyl-2-isopropyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one as a raw material, the same treatment as in Example 43 was performed to obtain the title compound in a yield 919%. Colorless needle-like crystals (chloroform-hexane). Melting point: 154.0-154.3 ° C ^ -NMRCCDCls) 5: 1.47 (6Η, d, J = 6.6 Ηζ), 3.03 (3Η, d, J: 5.0 Hz), 3.87 (3H, s), 5.36-5.52 (1Η, m), 7.00 (2H, d, J = 8.9 Hz), 7.85 (2H, d, J = 8.9

Hz), 8.66 (1Η, s), 9.77 (1H, br). II ^ KBOcm-1: 3262, 1677, 1547, 1518, 1417, 1310, 1269, 1250, 1 175, 1021, 831, 801. Mass spectrum (m / z): 301 (M +). Example 5 Production of 3 6- (3,4-dimethoxyphenyl) -2-isobutyl-4-methylamine formamidine-2H-pyridazin-3-one: As 4-ethoxycarbonyl- 6- (3,4-Dimethoxyphenyl) -2-isobutyl-2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 92.8%. Slightly yellow needle-like crystals (chloroform-hexane). Melting point: 111.4-112.6 ° C lH-NMR (CDCl3) 5: 1.01 (6Η, d, J = 6.6 Hz), 2.28-2.43 (1H, m), 3.03 (3Η, d, J = 5.0 Hz), 3.95 (3H, s), 3.97 (3Η, s), 4.16 (2H, d, J = 7.3Hz), 6.96 (1H, d, J = 8.6 Hz), 7.41-7.46 (2H, m), 8.68 (1H, s), 9.72 (1H, -52-) This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 5 Description of the invention (49 br) 〇IR (KBr) cm-1: 3276? 1683, 1585, 155 1, 1 5 12, 1257, 1227, 1171, 1118, 1021, 871. Mass spectrum (m / z): 345 ( M +). Example 5 4 6- (3-Fluoro-4_methoxyphenyl) -2-isobutyl-4-methylamine formamidine-2H-pyridazin-3-one Production: 6- (3 · Fluoro-4-methoxyphenyl) -2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 43 to obtain the title compound. Yield 88.3%. Pale yellow needle-like crystals (gas-form-hexane). Melting point: 153.3-154.9 ° C ^ -NMRCCDCls) 5: 1 · 〇〇 (6Η, d, J = 6.6Ηζ), 2.27 · 43 · (1Η5 m) 5 3.02 (3Η, d5 J = 5.0 Hz), 3.95 (3H, s), 4.15 (2H, d, J = 7.3 Hz), 7.00-7.08 (lH , M), 7.55 · 7.61 (1 Η, m), 7.65-7.72 (lH, m), 9.68 (1H, br). IR ^ KBOcnT1 ·· 3248, 1684, 1522, 1509, 1435, 1297, 1276. Mass spectrum (m / z): 333 (M +). Example 5 5 6- (3-Chloro-4-methoxyphenyl) _2-isobutyl-4-methylaminemethylamidino_2H-pyridazin-3-one: 6- (3-chloro -4 -methoxyphenyl) -2-isobutyl-4 -methoxythio-2H-pyrazin-3-one as a raw material, treated in the same manner as in Example 43 to obtain the title compound in a yield of 94_3%. -53- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (50) Micro-yellow needle-like crystals (chloroform-hexane)

Melting point: 181.8-183.5 ° C 1H-NMR (CDC13) δ · 1.0 · (6Η, d, J = 6.66 ζ), 2.27-2 · 43 (1Η, m), 3.02 (3Η, d, J = 5.0 Ηζ), 3.97 (3Η, s), 4.15 (2Η, d, J = 7.3 Ηζ), 7.01 (1Η, d, J = 8.6 Ηζ), 7.72 (1Η, dd , J = 2.3, 8.6 Ηζ), 7.85 (1Η, d, J = 2.3 Ηζ), 8.64 (1Η, s), 9.68 (1Η, br). IRCKBOcm · 1 · 3248, 1685, 1546, 1509, 1410, 1294, 1264. Mass spectrum (m / z): 351 (M +), 349 (M +). Example 5 6 Production of 2-isobutyl gastric 4-methylamine methylamidino-6- [4- (methylthio) phenyl] -2H_pyridazin-3-one: As 2-isobutyl- 4-methoxycarbonyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3 · one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 92.3%. Slightly yellow needle-like crystals (chloroform-hexane) Melting point: 129.6-130.6 ° C 1H-NMR (CDC13) 5: 1.00 (6Η, d, J = 6.6 Ηζ), 2.27-2 · 43 (1Η, m), 2.53 (3Η, s), 3.02 (3H, d5 J = 4.9 Hz), 4.16 (2Η, d, J = 7.3 Hz), 7.33 (2Η, d, J = 8.7 Hz) 5 7.80 (2H, d, J 8.7 Hz), 8.68 (1Η, s), 9.69 (1H, br). IR (KBr) cm_1: 3275, 1687, 1624, 1575, 1506, 1400, 1394. Mass spectrum (m / z): 331 (M +). Example 5 7 -54- ——----------- This paper size applies the Chinese National Standard (CNS) A4 specification (210 x 297 public directors) 1241295 A7 I ^ ————____ B7 V. Description of the invention ( 51) '~ —— _ 6- (4-Methoxyphenyl) -2- (3 · methyl_2_butenyl) _4 · Methylaminomethyl-2h • Pyridazine_ 3 -one : Using 4-ethoxycarbonyl-6- (4-methoxyphenylbenzene 2_ (3_methyl_2_butenylb 2h_pyridazin-3-one) as the raw material, the same treatment as in Example 43 was used to obtain The title compound, 79.0% yield. Yellowish needle-like crystals (chloroform-hexane). Melting point: 103.6-104.0 ° C 1H-NMR (CDC13) 5: L77 (3H, s), 1.88 (3Η, s), 3.02 (3Η, d, J = 5.0 Ηζ), 3.87 (3Η, s), 4.90 (2H, d, J = 7.3 Hz), 5.41-5_50 (1H, m), 6.99 (2Η, d, J = 8.9 Hz), 7.82 (2H, d, J = 8.9 Hz), 8.66 (1Η, s), 9.71 (1H, br). If ^ KBOcnT1: 3244, 1675, 1546, 1517, 1248, 1 175, 1025, 831, 798. Mass spectrum (m / z): 327 (M +). Example 5 8 6- (4-methoxyphenyl) -4-methylaminemethylmethyl-2- (2-pyridine) Production of methyl) aminomethylamidino_211_ pyridazin-3-one: (1) 6- (4-methoxyphenyl) -4 · methylaminomethylamidyl-2H · dathy-3 -Manufacture of the same: Using 4-ethoxycarbonyl-6- (4-methoxyphenyl) -2'-pyridazin-3-one as a raw material, the same treatment as in Example 4 3 ', the title compound, yield 9 7.9%. Colorless needle-like crystals (chloroform-hexane). Melting point: 246.5-246.9 ° C 1H-NMR (CDC13) (5: 3.06 (3Η, d, J 5.0 Hz), 3.87 (3Η, s ), 7 · 00 (2Η, d, J = 8.9 Hz), -55 · This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm) 1241295 A7 Description of the invention (52) ~~ " ~ ^ ~ — 7.83 (2Η, d, J = 8.9 Hz), 8.74 (1Η, s), 9.46 (1H, br), 11.89 (1H, br). IRCKBrOcm.1: 3219, 3142, 1675, 1568, 1518, 1257, 1226, 1184, 1032, 832. Mass spectrum (m / z): 259 (M +). (2) 2-ethoxycarbonylmethyl-6- (4-methoxyphenyl) -4- Production of methylamine methyl-2H-pyridazin-3-one: 6- (4-methoxyphenyl) -4-methylamine methylamidino-2H-pyridazin-3-one is used as the raw material, the same implementation Treatment of Example 47- (1) gave the title compound in a yield of 98 50/0. Melting point: 141.0-142.2 ° C lU ^ MR (COC \ 3) δ: 1.31 (3Η, t, J = 7.3 Hz), 3.01 (3H, d, J = 5.0 Ηζ), 3.87 (3Η, s ), 4 · 28 (2Η, q, J = 7.3 Ηζ), 5.02 (2Η, s), 6.99 (2Η, d, J = 8.9 Hz), 7.81 (2H, d, J = 8.9 Hz) , 8.72 (1Η, s), 9.47 (1Η, br). IRCKBOcm · 1: 3283, 1735, 1691, 1508, 1259, 1226, 1169, 1028. Mass spectrum (m / z): 345 (M +). (3) Manufacture of 6- (4-methoxyphenyl) -4-amidinomethylamidino-2- (2-pyridylmethyl) aminomethylamidino-2H-pyridazin-3-one: 2- Ethoxycarbonylmethyl-6- (4-methoxyphenyl) -4-methylaminemethylmethyl-211-pyridazin-3_one and 2- (aminemethyl) pyridine in xylene, at 15 ( ^ c was refluxed for 7 hours, and after-treatment was carried out in the same manner as in Example 47- (2) to obtain the title compound with a yield of 44.5%. Slightly yellow prisms (chloroform-hexane) -56- This paper size applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) 1241295 A7 —B7 V. Description of invention (53)

Melting point: 194.7_195.8 ° C ^ -NMRiCDCls) 5: 3.00 (3Η, t, J = 5.0 Ηζ), 3.87 (3Η, s) 5 4 · 62 (2Η, d, J = 5.0 Hz) , 5.06 (2H, s), 6.98 (2H, d, J = 8.9Hz), 7.15-7.21 (lH, m), 7.33-7_38 (1H, m), 7.35 (1Η, brt, J = 5.0 Hz ), 7.61-7 · 69 (1Η, m), 7.83 (2H, d, J = 8.9 Hz), 8.43-8 · 47 (1Η, m), 8.72 (1H, s), 9.49 (1H , B. IR (KBr) cm 1: 3283, 1681, 1664, 1518, 1251, 1167, 1024. Mass spectrum (m / z): 407 (M +). Example 5 9 2- (2-¾ethyl) Production of amine methyl-6- (4-methoxyphenyl) _4_methylamine medonyl_2H-pyridazin-3-one: 2 -ethoxycarbonylmethyl-6- (4-methyl Oxyphenyl) -4-methylamine methylamidino_211-pyridine-3 -one and 2-aminoethanol in a methanol solution under heating and refluxing for 4 hours, and the same post treatment as in Example 4 3 'to get the title Compound, yield 91.1%. Colorless fine needle-like crystals (chloroform-hexane)

Melting point: 240.2-241.2 ° C ^ -NMRCCDCls) (5 · 2.34 (1Η, t, J: 5.7 Hz), 2.98 (3Η, d, J = 5.1 Ηζ), 3_46-3 · 53 (2Η, m), 3 · 72-3 · 80 (2Η, m), 3.87 (3Η, s), 4.98 (2Η, s), 6.52 (1Η, br), 6.99 (2H, d, J = 8.9 Hz), 7.82 (2Η, d, J = 8.9 Hz), 8.70 (1H, s), 9.42 (1H, br). IR (KBr) cm_1: 3405, 3288, 1675, 1657, 1574, 1554 , 1519, 1508, 1416, 1402, 1253, 1074, 835. -57- _______________ This paper size applies to Chinese National Standard (CNS) A4 (210x 297 mm) 1241295 A7 __ B7 V. Description of the invention (54) Mass spectrum ( m / z): 360 (M +). Example 6 0 6- (4-methoxyphenyl) -4-methylaminemethylmethyl-2- [4_ (methylthio) aniline methyl]] Production of 2H-pyridazin-3-one: ι is 4 · methoxycarbonyl-6- (4- (methoxyphenyl) _2- [4_ (methylthio) aniline methylmethyl] -2H-pyridazine 3-Ketone was used as a raw material, and treated in the same manner as in Example 43 to obtain the title compound with a yield of 92.2%. Slightly yellow prisms (chloroform-hexane) Melting point: 230.6-232.0 ° C 1H-NMR (CDC13) 5: 2.46 ( 3H, s), 3.03 (3H, d, J = 5.0 Hz), 3.87 (3H, s), 3.98 (3H, s), 5.10 (2H, s) , 6.99 (2H, d, Bu 9.1 Hz), 7.23 (2H, d, J = 8.7 Hz), 7.46 (2H, d, J = 8.7 Hz), 7.84 (2H, d, Bu 9.1 Hz), 8.16 (1H, br) 5 8.74 (1Η, s), 9.42 (1Η, br). IR (KBr) cm-1: 3290, 3236, 1680, 1539, 1518, 1254. Mass spectrum (m / z) : 438 (M +). Example 6 1 Production of 2-cyclopropylmethyl-6- (4-methoxyphenyl) -cardiomethylaminomethyl-2-H-pyridazin-3-one: Propylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 89. 丨%. Slightly yellow needle-like crystals (methyl ether-ether) Melting point: 136.6-137.5 ° C 1H.NMR (CDC13) (5: -58-) This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (55) 0.47-0.62 (4H, m), 1.39-1.49 (1H, m), 3.03 (3Η, d5 J = 5_1 Hz), 3.87 (3Η, s), 4.18 (2H, d, J = 7.3 Hz), 7.0 (2Η, d, J = 8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.67 (1H, s), 9.72 (1H, brd, J = 5.1 Hz). IR (KBr) cm'1: 3339, 1684, 1627, 1609, 1518, 1252, 1183, 1027, 845, 836, 811. Mass spectrum (m / z): 313 (M +). Example 6 2 2-Cyclopropylmethyl-6- (3,4-dimethoxyphenyl) -4-methylaminemethylmethyl-2H-pyridazin-3-one Production: 2-Cyclopropylmethyl -6- (3,4-dimethoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 43 to obtain the title compound in a yield of 95.3%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 156.1-154.1 ° C 1H-NMR (CDC13) (5 · 0.4-0.65 (4H, m), 1.38-1 · 51 (1Η, m) , 3.03 (3Η, d, J = 5.0 Hz), 3.95 (3H, s), 3.97 (3H, s), 4.19 (2Η, d, J = 7.3 Hz), 6.96 (1Η, d , J = 8.9 Hz), 7.43 (1H, d, J = 2.3 Hz), 7.44 (1H, dd, J = 2.3, 8.9 Hz), 8.69 (1H, s), 9.72 (1Η, bi :). IR (KBr) cm · 1: 3267, 1686, 1552, 1520, 1508, 1422, 1255, 1232, 1034. Mass spectrum (m / z): 343 (M +). Example 6 3 2-cyclopropylmethyl-6 -(3 -Fluoro-4-methoxyphenyl) -4-methylaminemethyl-2-H-pyridazine_3_ -59- H-scale is suitable for national standards (CNS) A4 specifications (210X297 mm) ~ ~~~ _ ~ _ ~~ 1241295 A7 —---------------- _B7 V. Inventions ~~~ One ~ — One, the manufacture of ketones: _6_ (3_fluoro-4-methoxyphenyl) _ 'methoxy Carbonyl_2H • pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound with a yield of 90.3%. Pale yellow needle-like crystals (chloroform-hexane) Melting point: 139.6-140.7 ° C 1H-NMR (CDC13) (5: 0.45-0.64 (4H, m), 1.36_1.51 (ιη, m), 3.03 (3H, d, J = 5.0 Hz), 3.96 (3H, s), 4.18 (2H , D, J = 7.3 Hz), 7.01-7.08 (lH, m), 7.56-7.61 (1H, m), 7-65-7.72 (lH, m), 8.66 (1H, s), 9.69 (1H, br). IR (KBr) cm 1 · 3281, 1688, 1523, 1510, 1436, 1299, 1275. Mass spectrum (m / z) · 331 (M +). Example 6 4 6- (3-chloro-4-methoxybenzene ) -2-Cyclopropylmethyl_4-methylaminemethylfluorenyl · 2H-pyridazinone Production: 6- (3-chloro-4-methoxyphenyl) -2-cyclopropylmethyl-4 -Methoxycarbonyl-211-pyridol-3-one as a raw material, treated in the same manner as in Example 43 to obtain the title compound, yield 90.3%. ○ yellow needle-like crystals (chloroform-hexane). Melting point: 172.4-173.4 ° C 1H-NMR (CDC13) 5: 0.46--0.64 (4Η, m), 1.38-1.50 (1Η, m), 3.03 (3 (, d, J = 5.3 Hz), 3.97 ( 3H, s), 4.18 (2Η, d, J = 7.3 Hz), 7.02 (1Η, d, J = 8.8 Hz), 7.73 (lH, dd, J = 2.3, 8.8Hz), 7.95 (l H, d, J = 2.3Hz), 8.65 -60-This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (57) (1H, s), 9.68 (1H, br). H ^ KBOcnT1: 3244, 1684, 1552, 1509, 1410, 1294, 1264. Mass spectrum (m / z): 349 (M +), 347 (M +). Example 6 5 Production of 2-cyclopropylmethyl-4-methylaminemethylamidinyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3-one: 2-cyclopropylmethyl The compound 4-methoxycarbonyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3-one was treated in the same manner as in Example 43 to obtain the title compound in a yield of 94.3%. Yellow prism (chloroform-hexane) Melting point: 116.5-118.0 ° C ^ -NMRCCDCls) (5: 0.45-0 · 64 (4Η, m), 1.36-1 · 51 (1Η, m), 2 · 53 (3Η, s), 3.03 (3Η, d, J = 4.9 Hz), 4.18 (2H, d, J = 7.3 Hz), 7.33 (2Η, d, J = 8.7 Hz), 7.80 ( 2H, d, J = 8.7 Hz), 8.69 (1Η, s), 9.69 (1Η, br). IR (KBr) cm-1: 3275, 1686, 1625, 1595, 1545, 1505, 1400. Mass spectrum (m / z): 329 (M +). Example 6 6 2-Cyclopropylmethyl-4-ethylaminomethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one Production: 2-cyclopropylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one and 70% ethylamine aqueous solution in methanol, reacted at 70 In 4 hours, the same process as in Example 43 was carried out to obtain the title compound with a yield of 80.2%. Colorless needle-like crystals (chloroform-hexane) -61-This paper size is in accordance with China National Standard (CNS) A4 (21 × 297 mm) ) 1241295 A7 V. Description of the invention (58) Melting point: 136.3-136.9 ° C 1H-NMR (CDC13) 5: 0.47-0 · 64 (4Η, m), 1.28 (3Η, t, J = 7.4 Hz ), 1.37-1 · 53 (1Η, m), I 3.51 (2Η, d, J = 8.9 Hz), 3.87 (3Η, s), 4.18 (2H, d, J = 7_3 Hz), 7.00 (2 H, d, J = 8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.68 (1H, s), 9.76 (1 (, brt5 J = 5.9 Hz) IRCKBOcm · 1: 3211, 1679, 1622, 1610, 1517, 1417, 1249, 1182, 1033, 834. Mass spectrum (m / z): 327 (M +). Example 6 7 2_cyclopropylmethyl · 6_ (4_methoxyphenyl) -4 -Production of n-propylamine methylamidino-2H-pyridazin-3-one: 2-cyclopropylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-sulfur-3- A ketone and n-propylamine-methanol solution were used as raw materials, and were treated in the same manner as in Example 43 to obtain the title compound in a yield of 65.4%. Colorless needles (chloroform-hexane). Melting point: 101.3-101.6 ° C ^ -NMRiCDCls) (5 : 0 · 46_0.63 (4Η, m), 1.01 (3H, t, Bu 7 · 3 Ηζ), 1.39-1_52 (1Η, m), 1.60-1 · 76 (2Η, m), 3 44 (2Η, d, J = 6.9 Hz), 3.87 (3H, s), 4.18 (2H, d, J = 7.3 Hz), 7.00 (2H, d, J = 8.9 Hz), 7.83 (2Η, d, J = 8.9 Hz), 8.68 (1H, s), 9.81 (1H, br). IR (KBr) cm'1: 3216, 1679, 1622, 1608, 1517, 1416, 1252, 1182, 1033, 833 o -62- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (59) Mass spectrum (m / z): 341 (M +). Example 6 8 Production of 4-benzylaminemethylamidino-2-cyclopropylmethyl-6- (4-methoxyphenyl) -2pyridazine_3_remuneration: 2-cyclopropylmethyl-4 -Ethoxycarbonyl-6- (4-methoxyphenyl) _2Η-zine with 65 mg (0.20 mol) in xylene (1 ml), plus 318 mg (2.97 mol) ), At 140. (: Stir off for 24 hours. Add 20 ml of ethyl acetate to the reaction solution, wash in the order of 2N HC1 (20 ml), saturated brine (20 ml), and dry over anhydrous NajCU. The solvent is distilled off, and the residue obtained is 98 mg of the product was crystallized from chloroform-hexane, and 72 mg (93.4%) of the title compound was obtained as light yellow fine needle crystals. Melting point: 119.7-120.1 ° C 1H-NMR (CDC13) δ: 0.44-0.62 (4H , M), 1.37-1.50 (1H, m), 3.89 (3Η, s), 4.16 (2Η, d5 J = 7.3 Ηζ), 4.67 (2Η, d, J = 5.9 Ηζ), 7.00 (2Η , D, J = 8.8 Hz), 7.24-7 · 41 (5Η, m), 7.83 (2Η, d, J = 8.8 Hz), 8.71 (1H, s) 5 10.18 (1H, brt, J = 5.9 Hz). IR (KBr) cm · 1: 3210, 1675, 1622, 1610, 1516, 1274, 1250, 1185, 1028, 838. Mass spectrum (m / z): 3 89 (M +). Example 6 9 2- Cyclopropylmethyl-6- (4-methoxyphenyl) -4- (2-pyridylmethyl) aminomethyl-2H-pyridazin-3-one: 2-Cyclopropylmethyl-4 -Ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one-63- This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 mm)

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Line 1241295 A7 B7 V. Description of the invention (60 and 2- (aminemethyl) pyridine were reacted in xylene at 140 for 1 hour, and treated as in Example 58- (3) to obtain the title compound in a yield of 84.2. / 〇. Slightly yellow needle-like crystals (chloroform-hexane) Melting point: 98.6-99.3 ° C lH-NMR (CDCl3) 5: 0.46-0.63 (4H, m), 1.39-1 · 55 (1Η, m) , 3.87 (3Η, s), 4.20 (2H, d, J = 7.3 Hz), 4.83 (2Η, d5 J = 5.4 Hz), 7.00 (2Η, d, J = 9.3 Hz), 7 · 17-7 · 23 (1Η, m), 7.32-7 · 37 (1Η, m), 7.63-7.71 (1H, m), 7.83 (2Η, d, J = 9.3 Hz), 8.61- 8.65 (1Η, m), 8.71 (1H, s), 10.55 (1Η, brt, J = 5.4 Hz) IR (KBr) cm · 1: 3252? 1683, 1624, 1609, 1516, 1417 , 1273, 1253, 1181, 1022, 834. Mass spectrum (m / z): 390 (M +). Example 7 0 2-Cyclopropylmethyl winter (4-methoxyphenyl) -4- (4-pyridyl) ) Manufacture of Carbamidyl-2H-pyridazin-3-one: NaH was added to 34 mg of 4-aminopyridine (0.531 mol) to dimethylarsine (0.5 ml) / spring solution. (Washed with toluene to remove oil) 9 mg (0.38 mmol) was stirred at room temperature for 15 minutes, and Add 2-cyclopropylmethyl-4-ethoxycarbonyl · 6- (4-methoxyphenyl) -2H-pyridazin-3-one (80 g) (0.24 mmol) and stir at the same temperature for 30 minutes 30 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with water (20 ml) and saturated brine (20 ml) in that order, and then dried without drying. Distilling off the remaining 61 mg of the solvent, it was separated into silica gel. Chromatography (development, separation, purification, chloroform / methanol (1/10/1) was used to separate and purify the title compound 6 1 mmol 2 -64-This paper is in accordance with China National Standard (CNS) A4 (210 X 297) (Centimeter)

Hold

1241295

AT —— _ B7 V. Description of the invention (61) (61.1%) 〇 Pale yellow fine needle-like crystals (chloroform-hexane) Melting point: 181.3_181.5 ° C 1H-NMR (CDC13) (5: 〇.49_0 68 (4Η, m) 5 1.40-1.56 (1H, m), 3.89 (3Η, s), 4.24 (2Η, d, J = 7.3 Hz), 7.02 (2Η, d, J = 8.9 Hz), 7.69 (2Η, d5 J = 6.3 Hz), 7.85 (2H, d, J = 8.9 Hz), 8.57 (2H, d, J = 6.3 Hz), 8.75 (1Η, s), 12.25 (1H, br). IRCKBOcnT1: 1697, 1629, 1607, 1517, 1273, 1254, 1184, 1017, 835, 813, 805, 791. Mass spectrum (m / z): 376 (M +). Example 7 1 2 -% Propylmethyl-6- (4-methoxyphenyl) -4-anilinemethyl-2H-pyridazin-3_one production: 2-cyclopropylmethyl_4_ethoxycarbonyl_6_ (4_methoxyphenyl) _2H • pyridazin-3-one and aniline were treated in the same manner as in Example 70 to obtain the title compound in a yield of 12 2/0. Pale yellow slightly like needle-like crystals (chloroform-hexane Alkane) Melting point: 162.8-163.3 ° C 1H-NMR (CDC13) δ: 0.49-0.67 (4H, m), 1.41-1.68 (1Η, m) 5 3.88 (3Η, s), 4.23 (2Η, d, J = 7.3 Ηζ), 7.01 (2Η, d, Bu 8.9 Ηζ), 7.13-7 · 20 (1Η, m), 7.34-7.42 (2Η, m), 7.75-7 · 8 1 (2Η, m) 5 7 · 85 (2Η, d, J = 8.9Ηζ), 8.77 (1Η, s), 12.00 (1Η, br). IRCKBOcrxT1: 3189, 1687, 1602, 1518, 1274 ， 1254，1184, -65-" —--^-_ This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 1241295 A7 _______ B7 V. Description of the invention (62) 1025, 834, 804 , 791 ° Mass spectrum (m / z): 375 (M +). Example 7 2 2-Cyclopentyl-6- (4-methoxyphenyl) -4-anilinomethyl-2H-pyridazinone Production: Using 2-¾pentylmethyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-p dadazone-3-one as a raw material, the same treatment as in Example 43 was performed to obtain the title compound, Yield 75 2〇 / 〇. Colorless needle-like crystals (chloroform · hexane) Melting point · 107.4-107.8 ° C ^ -NMRCCDCls) (5: 1 · 30-1 · 45 (2Η, m), 1 · 50- 1.82 (6Η, m), 2.47-2 · 64 (1Η, m), 3.02 (3H, d, J = 5.0 Hz), 3.87 (3H, s), 4.27 (2Η, d5 J2 7.6 Hz), 7.00 (2Η, d, J = 8.9 Hz), 7.83 (2H, d, J = 8.9 Hz), 8.66 (1Η, s), 9.74 (1H, br). IR (KBr) cm-1: 3218, 1679, 1624, 1611, 1560, 1550, 1517, 1414, 1249, 1188, 1138, 1030, 844, 802. Mass spectrum (m / z): 341 (M +). Example 7 3 Production of 2-cyclopentylmethyl-4-ethylaminemethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-cyclopentylmethyl-4 -Ethoxycarbonyl-6- (4-methoxyphenyl)-2H-stilbene-3-hydrazone was treated with 70% ethylamine aqueous solution in methanol and treated in the same manner as in Example 43 to obtain the title compound, yield 82.2 %. Colorless needle-like crystals (chloroform-hexane) 66- The paper size is applicable to China National Standard (CNS) A4 (2i0x 297 mm) 1241295 A7 V. Description of the invention (63) Melting point: 129.1-129.4 ° C ^- NMRCCDCls) 5: 1.27 (3Η, t, J = 7.3 Ηζ), 1.34-1 · 45 (2Η, m), 1.50-1 · 82 (6Η, m), 2.48-2 · 65 ( 1Η, m), 3.44-3 · 56 (2Η, m), 3.87 (3Η, s) 5 4 · 27 (2Η, d, J = 7.6 Hz), 6.99 (2H, d, J = 8.9 Hz), 7.82 (2Η5 d5 JU Hz), 8.67 (1H, s), 9_76 (1H, br). IRCKBrOcnT1: 3242, 1683, 1623, 1609, 1518, 1417, 1311, 1249, 1 181, 1033, 834, 800 Mass spectrum (m / z): 355 (M +). Example 7 4 Production of 2-cyclopentylmethyl-6- (4-methoxyphenyl) _4-n-propylaminemethylamidino-2H-pyridazin-3-one: 2-cyclopentylmethyl-4- Ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 67. The yield was 79.1%. Colorless needle-like crystals (chloroform-hexane) Melting point: 109.9-110.2 ° C ^ -NMRCCDCls) 5: 1.01 (3Η, t, J = 7.3 Ηζ), 1.3 · 1-1 · 46 (2Η, m), 1.50-1.83 (8H, m), 2.48-2.65 (1Η, m), 3.44 (2H, q, J = 6.4 Hz), 3.87 (3H, s), 4.27 (2H, d, J = 7.6 Hz), 7.00 (2H, d, J = 8.9 Hz), 7.82 (2Η, d5 J = 8.9 Hz), 8.67 (1H, s), 9.81 (1H, br). IR (KBr) cm · 1: 3246? 1683, 1 544, 15 19, 1417, 13 11, 1273, 1252, 1030, 835, 797. Mass spectrum (m / z): 369 (M +). -67- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (M Example 7 5 4-Benzylamine methylamido-2-cyclopentylmethyl- Production of 6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-Cyclopentyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridine The azinone and amidine were reacted in xylene at 140 ° C for 2 hours, and treated as in Example 68 to obtain the title compound in a yield of 78.5%.

Light yellow needle-like crystals (chloroform-hexane) Melting point: 107.6-108.1 ° C ^ -NMRCCDCls) δ: 1.28-1.44 (2H, m), 1.48-1.8 1 (6Η? M)? 2.46-2.63 (1Η5 m )? 3.87 (3Η, s), 4.25 (2Η, d5 J = 7.6 Ηζ), 4.66 (2Η, d, J = 5.9 Ηζ), 7.00 (2H, d, J = 8.9 Hz), 7. · 23-7 · 40 (5Η, m) 5 7 · 82 (2Η, d, J 2: 8 · 9

Hz), 8.70 (1H5 s), 10.18 (1Η, brt5 J = 5.9 Hz). IRCKBOcnT1: 3251, 1677, 1624, 1611, 1517, 1386, 1259, 1 179, 1 136, 1033, 83 1.

Mass spectrum (m / z): 417 (M +). Example 7 6 Production of 2-cyclopentylmethyl-6- (4-methoxyphenyl) -4- (2-pyridylmethyl) aminomethane-2H-pyridazin-3-one: 2- Cyclopentyl-4-ethoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 58- (3) to obtain the title compound in a yield 88.6%. Colorless needle-like crystals (chloroform-hexane)

Melting point: 126.6-127.5 ° C -68-The size of this paper applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (65) 1H-NMR (CDC13) 5: 1.30 -1 · 46 (2Η, m), 1.49-1 · 82 (6Η, m), 2.50-2.67 (1H, m), 3.87 (3H, s), 4.29 (2H, d, J = 7.6 Hz) , 4.82 (2H, d, J = 5.3 Hz), 7.00 (2H, d, J = 8.9 Hz), 7.16-7.23 (1H, m), 7.31-7.36 (1H, m), 7.62-7 · 70 (1Η, m), 7.83 (2Η, d, J = 8.9 Hz), 8.60-8.64 (lH, m), 8.69 (1H, s), 10.53 (1H, brt, J = 5.3 Hz). IRCKBrOcm · 1: 3255, 1673, 1624, 1610, 1511, 1457, 1433, 1259, 1251, 1028, 832. Mass spectrum (m / z): 418 (M +). Example 7 7 Production of 4-benzylamine formamyl-6- (4-methoxyphenyl) -2-methyl-2H-pyridazin-3-one: 4-ethoxycarbonyl-6- (4 -Methoxyphenyl) -2-methyl-2H-pyridazin-3-one and benzylamine in xylyl, reacted at 140 ° C for 1 hour, and treated as in Example 68 to give the title compound in a yield 94.2%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 144.8-145.8 ° C lH-NMR (CDCl3) 5: 3.87 (3Η, s), 3.94 (3Η, s), 4.67 (2Η, d, J = 5.9 Ηζ), 7.0 (2Η, d, J = 8.9 Hz), 7.23-7.40 (5H, m), 7.82 (2H, d, J = 8.9 Hz), 8.71 (1H, s), 10 · 13 (1Η, brt, J = 5.9 Hz) o IR (KBr) cm'1: 3244, 1679, 1624, 1 583, 1516, 1455, 1251, 1182, 1030, 836. Mass spectrum (m / z): 349 (M +). -69- This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (66 Example 7 8 6- (4-methoxyphenyl) -2-methyl Production of 4- (2-pyridylmethyl) aminomethylamidino-2H-pyridazin-3-one: 4-ethoxycarbonyl-2-methyl-6- (4-methoxyphenyl) -2H -Pyridazin-3-one as a raw material, treated in the same manner as in Example 58- (3) to obtain the title compound with a yield of 861%. Pale yellow needle-like crystals (chloroform-hexane). Melting point: 122.4-122_9 ° C NMRCCDCls) 5: 3.87 (3Η, s), 3.97 (3Η, s), 4.82 (2Η, d, J = 5.6 Ηζ), 7.00 (2Η, d

J = 8.9 Hz), 7.17-7 · 23 (1Η, m), 7.31-7 · 36 (1Η, m), 7.63-7.71 (1H, m), 7.82 (2H, d, J = 8.9 Hz), 8.61-8.65 (1H, m), 8.71 (1H s), 10,53 (1H, brt, J = 5.6 Hz) o IR (KBr) cm · 1: 3238? 1683, 1625, 1613, 1516, 1435, 1248, 1180, 1035, 836. Mass spectrum (m / z): 350 (M +). Example 7 9 2-Methenyl-6- (4-methoxyphenyl) -4-methylaminemethanemethyl-2H-pyridazin-3-one and 2-methyl-4-dimethylaminocarboxylic acid- Production of 6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-Benzyl-4-ethoxycarboxy-6- (4-methoxyphenyl) -2H_pyridazine · 3-ketone 7 1 gram (0.19 mmol) was added to 3 liters of a 40% aqueous solution of diamidine and stirred at room temperature for 17 hours. 74 g of the residue obtained by distilling off the solvent was separated and purified by silica gel fractionation chromatography (developing solvent: chloroform / methanol (20/1), and the title compound (2-fluorenyl- 6- (4-methoxyphenyl) _4_methylamine formamyl_ 211-pyridazine_3-one) 29.4 mg (44.7%). -70- This paper size applies to the Chinese standard (CNSy A4 specification (210X 297 mm) 1241295 A7 B.7 V. Description of the invention (67) Pale yellow needle-like crystals (chloroform-hexane) Melting point: 181.7-182.1 ° C ^ -NMRCCDCls) 5: 3.00 (3Η, d, J = 4.9 Ηζ), 3.87 (3Η, s) 5 5.47 (2H, s), 7.00 (2Η, d, J = 8.8 Hz), 7.30 · 7 · 36 (2Η, m), 7.47 (2H , D, J = 6.4 Hz), 7.84 (2H, d, > 9.3 Hz), 8.67 (1H, s) 5 9.65 (1H, br). IRCKBiOcm · 1: 3270, 1680, 1607, 1518, 1408, 1251 , 1026, 850, 743 ° From the chromatographic fraction with a small Rf value, the title compound (2 · fluorenyl-6- (4-methoxyphenyl) -4_ (dimethylaminemethylfluorenyl) -2H_ Pyridazin-3-one) 10.5 mg (14.8%). Colorless fine needle-like crystals (chloroform-ether-hexane). Melting point: 183.0-184.0 ° C lH ^ UK (COC \ 3) δ: 2.96 (3H, s) 5 3 · 11 (3Η, s), 3. 86 (3H, s), 5.41 (2Η, s), 6.97 (2Η, d, J = 9.0 Ηζ), 7.26-7.33 (3Η, m), 7.50 (2Η, dd5 J = 2.0, (8.0 Hz), 7.72 (2H, d, J = 9.0 Hz), 7.74 (1Η, s). IRCKBOcnT1: 1654, 1641, 1610, 1521, 1250, 1025, 832. Example 8 0 6- ( Production of 4-methoxyphenyl) -4-methylamine formamyl-2_ (4-nitrobenzyl) -2H-pyridazin-3 · one: 4-methoxycarbonyl-6- (4-methoxy Phenyl) -2- (4-nitropyridyl) -2Η-pyridazin-3-one was treated in the same manner as in Example 43 to obtain the title compound with a yield of 92.2%. Male needle-like crystals (chloroform-hexane burn)

Melting point 198.8-199.4 ° C -71-This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (68) 1H-NMR (CDC13) 5: 3 · 01 (3Η, d, J = 5.0 Hz), 3.88 (3Η, s), 5.54 (2H, s), 7.01 (2H, d, J = 9.2 Hz), 7.62 (2H, d, J = 8.9 Hz ), 7.82 (2H, d5 J = 9.2 Hz), 8.22 (2H, d, J = 8.9 Hz), 8.71 (1H, s), 9.48 (1H, br). IRCKBOcm · 1 · 3282, 1680, 1515, 1344, 1254. Mass spectrum (m / z): 394 (M +). Example 8 1 Production of 6- (4-methoxyphenyl) -4-methylamine formamidine-2- [4- (3-pyridylcarbonylamino) benzyl] _ 2H-pyridazin-3-one : Using 4-methoxycarbonyl-6- (4-methoxyphenyl) -2- [4- (3-pyridylcarbonylamino) fluorenyl] -2H-pyridazin-3-one as the raw material, the same as the example Treatment of 43 gave the title compound in a yield of 92.7%. Slightly yellow fine needle-like crystals (chloroform-hexane) Melting point: 226.7-227.6 ° C lR ^ MR (COC \ 3) δ: 3.00 (3Η, d, J = 5.0 Hz), 3.87 (3H, s) 5 5.46 (2Η, s), 7.00 (2Η, d, J = 9.0 Hz), 7.44 (1Η5 ddd, J 2 1.1, 4.6, 6.8 Ηζ), 7.53 (2Η, d, J = 8.5 Ηζ), 7.63 (2Η, d, J = 8.5 Ηζ), 7.83 (2Η, d, J = 9.0 Ηζ), 7.87 (1Η, br), 8.19 (2Η, ddd , J = 1.6, 1 · 7, 8 · 1 Hz), 8.66 (1H, s), 8.78 (1H, dd, J = 1.7, 4 · 6 Hz), 9 · 08 (1Η, dd, J = 11, 1.6 Hz), 9.62 (1Η, brq, J = 5.0 Hz). IRCKBOcnT1: 3339, 1679, 1601, 1535, 1515, 1412, 1317, 1253. Mass spectrum (m / z): 469 (M +). -72- This paper size applies Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 V. Description of the invention (69) Example 8 2 2- (2,4-dichlorobenzyl) _6_ (4_ Production of methoxyphenylmethylamine methylamidino-2h_pyridazine-one -2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 43 to obtain the title compound in a yield of 97.4%. Pale yellow fine needle-like crystals (chloroform-hexane). Melting point: 154.2-156.2. (: 1H -NMR (CDC13) δ: 3.0 · 1 (3Η, d, J = 5.0Ηζ), 3.86 (3Η, s), 5.57 (2Η, s), 6.98 (2H, d, J = 8.9 Hz ), 7.16 (1H5 d, J = 8.3 Hz), 7.22 (1Η, dd5 J = 2.0, 8.3 Hz), 7.45 (1Η, d, J = 2.0 Hz), 7.79 (2Η, d, J = 8.9 Hz), 8.72 (1H, s), 9.54 (1H, br). IR (KBr) cm · 1: 3288, 1683, 1629, 1610, 1592, 1474, 1516, 1411, 1255, 1 165, 834 〇 Mass spectrum (m / z): 421 (M +), 419 (M +), 417 (M +). Example 8 3 6- (4-methoxyphenyl) -4-methylaminemethylmethyl-2- (3 -Pyridylmethyl) -2H-pyridazin_3-one production: 4-methoxycarbonyl-6- (4-methoxyphenyl) -2- (3-pyridylmethyl)- 2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 87.7%. Pale male needle-like crystals (chloroform-hexane) Melting point: 153.8-154.3 It (decomposed) -丨..-This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (70) lU-NMR (COCl3) δ: 3.01 (3Η, d5 J 2 5.0 Ηζ), 3.87 (3Η, s), 5.47 (2Η, s) 5 7.00 (2Η, d, J = 9.1 ， ζ), 7.25-7 · 32 (1Η, m), 7.78 -7 · 85 (3Η, m), 8.56-8.59 (1Η, m), 8.67 (1Η, s), 8.77-8.80 (1Η, m), 9.55 (1Η, br). IR (KBr) cm ' 1: 3253, 1679, 1547, 15 18, 1417, 1316? 1251, 1028, 833, 796 ° Mass spectrum (m / z): 350 (M +). Example 8 4 Production of 2-cinnamyl-6- (4-methyllactate) -4-methylaminemethyl-copper-copper: 2 · cinnamyl-4-ethoxycarbonyl-6- (4-methyl Oxyphenyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 43 to obtain the title compound in a yield of 1000/0. Pale yellow prisms (chloroform-acetic acid-hexane) Melting point: 160.0-161.0 ° C 1H-NMR (CDC13) 5 · 3 · 02 (3Η, d, J = 5.1 Ηζ), 3.86 (3Η, s), 5.07 (2Η, dd, J = 1.2, 6.6 Hz), 6.43 (1H, td, J = 6.6, 15.8 Hz), 6.73 (1H, d, J = 15.9 Hz), 6.99 (2H, d, J2 8.8 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.23-7 · 34 (3Η, m), 7.40 (2Η, dd, J = 1.2, 8.1 Hz), 7.83 (2H, d , Bu 9.0 Hz), 8.68 (1H, s), 9.66 (1H, brs).

Ii ^ KBOcm · 1: 3245, 1686, 161 1, 1516, 1024, 835. Example 8 Production of 5- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4-methylaminemethylamidino-2H-pyridazin-3-one: -74- _____ ___- --- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 ___ B7 Note —… --—— ~~ — ~ — With 2- (4-chlorocinnamyl) _4- Ethoxycarbonyl-6_ (4-methoxyphenyl) _2Η_pyridazine ·% ketone was used as a raw material, and treated in the same manner as in Example 43 to obtain the title compound in a yield of 93.3%. Light yellow fine needle-like crystals (chloroform-hexane) Melting point: 184.2-185.4 ° C ^ -NMRCCDC ^) δ: 3.03 (3Η, d, J = 4.6 Ηζ), 3.87 (3Η, s), 5 · 06 (2Η, d, J = 6.6 Ηζ), 6. · 40 (1Η, td, J = 6.6, 15.8 Ηζ), 6.67 (1d, d, J = 15.8 Ηζ), 7.00 (2Η, d, J = 8.6 Ηζ), 7.27 (2Η, d, J = 8.6 Ηζ), 7.33 (2Η, d, J = 8.6 Hz), 7.84 (2Η, d, Bu 8.6 Hz), 8.69 (1H, s), 9.63 (1H, brd, J = 4.6 Hz). IR (KBr) Cm-i: 3246, 1677, 1550, 1519, 1491, 1402, 1260, 1186, 1158, 1029, 841. Mass spectrum (m / z): 411 (M +), 409 (M +). Example 8 Preparation of 6 4-carboxy-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazin-3-one in 2- (4-chlorocinnamyl)- To a suspension of 1.35 g (3.29 mmol) of 4-methoxycarbonyl-6- (4-methoxyphenyl) 2pyridazinone in methanol (50 ml), 20 ml of 4N aqueous NaOH solution was added at room temperature. , Stir for 30 minutes at the same temperature. Remove 100% of the methanol 'residue under reduced pressure and add 100 halo; raise the water, make it acidic with HQ under ice-water cooling, extract with chloroform, and wash the organic layer with saturated brine. After cleaning, take anhydrous

NajCU is dry. The solvent was distilled off, and the title compound h30 g (99.7%) was obtained as yellow crystals. -75- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Order

Line 1241295 A7 β7 V. Description of the invention (72) Melting point: 222.6-224.0 ° C (decomposition) ^ -NMRCCDCls) 5 · 3.88 (3Η, s), 5.10 (2Η, d, J = 6.8 Ηζ), 6.40 (1Η, td, J = 6.8, 15.6 Hz), 6.74 (1Η, d, J = 15.6 Hz), 7.01 (2H, d, J = 8.8 Hz), 7.34 (2Η, d, J = 8.8 Hz), 7.81 (2H, d, J = 8.8 Hz), 8.65 (1H, s), 14_10 (1H, brd). IR (KBr) cm · 1: 1743, 1630, 1609, 1561, 1518, 1475, 1420, 1252, 1029, 900, 837, 814. Mass spectrum (m / z): 398 (M +), 396 (M +). Example 8 7 Production of 2- (4-chlorocinnamyl) -4-ethoxycarbonylamino-6- (4-methoxyphenyl) -2H-pyridazin-3-one: In 4- 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-serum_3_one 657 mg (1.66 mmol) in benzene (15 ml) suspension at room temperature Add 168¾ g (1.66 ¾ mole) of diethylamine and 456 mg (1.66 mmol) of diazine to test the diphenyl scale. After stirring at the same temperature for 30 minutes, heat and reflux at 1000 ° C for 30 minutes. . Next, 20 ml of ethanol was added to the reaction solution, and the mixture was heated under reflux at 100 ° C for 15 hours. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (500 g of silica gel, hexane / ethyl acetate (3/1)), and then crystallized from chloroform · hexane to give a yellowish color Fine needle crystals gave 327 mg (44.9%) of the title compound. Melting point: 171.2-172.1 ° C ^ -NMRCCDCls) 5: 1.34 (3Η, t, J = 7.1 Hz), 3.86 (3Η, s) 5 4.28 (2H, q, J = 7.1 Hz), 4.99 (2Η, dd, J = 1.0, 6.3 Hz), 6.40 (1H, td, J = 6.3, 15.9 Hz), -76 -L.. This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 V. Description of the invention (73) 6.65 (1H, td, J = 1.0, 15.9 Hz), 6.96 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.31 (2Η, d, J = 8.6 Hz), 7.78 (2H, d, J = 8.8 Hz) , 8.08 (1H, brs), 8.26 (1H, s). IR (KBr) cm · 1: 3224, 1727, 1642, 1606, 1540, 1518, 1491, 1256, 1225, 1177, 830. Mass spectrum (m / z): 441 (M +), 439 (M +). Example 8 8 Production of 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4-isopropoxycarbonylamino_2H-pyridazin_3-one: With 4-carboxy- 2- (4-chlorocinnamyl) · 6 · (4 · methoxyphenyl) -2H-pyridazin-3-one was treated in isopropanol as in Example 87 to obtain the title compound. The rate is 41.4%. Light yellow fine needle-like crystals (chloroform-hexane) Melting point: 123.9-127.4t: ^ -NMRCCDCls) 5: 1.33 (6H, d, J = 6.4 Hz), 3.86 (3H, s) 5 4.97-5.10 (3H, m), 6.40 (1H, td, J = 6.4, 15.9 Hz), 6.64 (1Η, td, J = 1.2, 15.9 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.29 (2H , D, J = 8.9 Hz), 7.30 (2H, d5 J = 8.9 Hz), 7.30 (2H, d, J = 8.9 Hz), 7.79 (2H, d, J = 8.9 Hz), 8.03 (1H, brs) , 8.26 (1H, s). IR (KBr) cm · 1: 3370, 3056, 1732, 1645, 1613, 1535, 1518, 1497, 1256, 1178, 1111, 832. Mass spectrum (m / z): 455 (M +), 453 (M +). Example 8 9 -77- This paper size applies to Chinese National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7

Production of 4-n-butoxy-amino-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2 fluorene-aginin-3 ketone: 4-carboxy-2- (4 · Chlorocinyl) -6- (4-methoxyphenyl) _2H-pyridazin-3-one as a raw material, treated with n-butanol in the same manner as in Example 87 to obtain the title compound in a yield of 37.3%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 150.2-150.9 ° C ^ -NMRCCDCls) 5: 0.96 (3Η, t5 J = 7.47.4ζ), 1.35-1 · 50 (2Η, m), 1.63-1 · 75 (2Η, m), 3.86 (3Η, s), 4.23 (2Η, t, J = 6.6 Hz), 4.99 (2Η, dd, Bu 1.2, 6.4 Hz) , 6.40 (lH5td, J = 6.4, 15.8HZ), 6.64 (lH, td, J = 1.2, 15.8 Hz), 6.96 (2H, d5 J = 8.9 Hz), 7.27 (2H, d5 J = 8.9 Hz), 7 · 30 (2Η, d, J-8.9 Hz), 7.78 (2Η, d, J = 8.9 Hz), 8.08 (1Η, brs), 8.26 (1H, ten IR (KBr) cm · 1: 3223 , 3031, 1728, 1641, 1606, 1541, 1516, 1491, 1247, 1220, 1181. Mass spectrum (m / z): 469 (M +), 467 (M +). Example 9 0 4-Ethoxycarbonylamino- Production of 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) _2H-pyridazin-3-one: 4- (4-chlorocinnamyl) -6- ( 4-methoxyphenyl) -2H-pyridazin-3-one as a raw material was treated in benzyl alcohol in the same manner as in Example 87 to obtain the title compound in a yield of 12.1%. Pale yellow fine needle-like crystals (chloroform_hexane Alkanes) _________ -78- The paper size is suitable for financial and household materials (CNS) A iron grid (coffee X 297 public compound) 1241295 A7 B7 ^ V. invention ~~~~~ Point: 190.5-191.7 ° C ^ -NMRCCDCls) 5 · 3 · 85 (3Η, s), 4.98 (2H, dd, J = 1.0, 6.4 Hz), 5_25 (2H, s) 5 6.39 (1H, td , Bu 6.4, 15.9 Hz), 6.63 (1H, td5 J = 1.05 15.9 Hz), 6.96 (2H, d, J = 9.0 Hz), 7.29 (2Η, d, J = 8.8 Hz), 7_30 (2H5 d , J = 8.8 Hz), 7.32-7 · 44 (5Η, m) 5 7 · 77 (2Η, d, J = 9.0 Hz), 8.17 (1H, brs), 8.26 (1H, s). IR (KBr) cm · 1: 323 1, 3034? 1729, 1640, 1607, 1540, 1516, 1252, 1223, 1210. Mass spectrum (m / z): 503 (M +), 501 (M +). Example 9 1 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4- [4- (methylthio) benzyloxycarbonylamino] _ 2H-pyridazin-3-one Production: 4-carboxy-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazin-3-one as raw material, 4- (methylthio) benzyl alcohol In the same manner as in Example 87, the title compound was obtained in a yield of 46.0%. Light yellow fine needle-like crystals (chloroform-hexane) Melting point: 187.6-188.7 ° C lH ^ UR (COCl3) δ: 2.49 (3 (, s), 3.85 (3H, s), 4.98 (2Η, dd , J = 1.2, 6.4 Ηζ), 5.20 (2Η, s), 6.39 (1Η, td, J = 6.4, 15.9 Ηζ), 6.42 (1Η, td,] = 1.2, 15.9 Ηζ), 6 · 96 (2Η, d, J = 8.9Ηζ), 7.23-7.36 (8Η, m), 7.77 (2Η, d, J-8.9Ηζ), 8.15 (1Η, brs), 8.24 (1Η, s). IF ^ KBOcm-1: 3224, 3028, 1729, 1640, 1605, 1541, 1518, -79- This paper size applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1241295 A'7 _________ B7 V. Description of the invention (76) 1501, 1491, 1252, 1176. Mass spectrum (m / z): 549 (M +), 547 (M +). Example 9 Production of 2 4-carboxy-6- (4-methoxyphenyl) _2- (3-methyl-2-butynyl) -2H-pyridazin-3-one: Methoxyphenyl) -4-ethoxyl-2 · (3-methyl-2-butenyl) -2H-pyridazin-3_one was used as the raw material, and treated in the same manner as in Example 86 to obtain the title compound. Yield: 93.1%. Light yellow needle-like crystals (chloroform-hexane). Melting point: 153.5-156.6. (: 1H-NMR (CDC13) δ:! · 78 (3Η, s), 1.88 (3Η, s), 3.87 (3H, s), 4.94 (2H, d, J = 6,8 Hz), 5.38 -5.54 (1Η, m), 7.01 (2Η, d, J = 8.8 Hz), 7.80 (2H, d, Hz), 8.62 (1H, s), 14.27 (1H, br). IR (KBr ) cm]: 1740, 1653, 1629, 1609, 1517, 1477, 1420, 1252, 900. Mass spectrum (m / z) · 314 (M +). Example 9 3'ethoxycarbonylamino 4- (4- Production of methoxyphenyl) -2- (3-methyl-2-butylfluorenyl) _2H_pyridine-3-_: 4-carboxy-6- (4 · methoxyphenyl) -2- (3- Methyl-2-butenyl) _2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 87 to obtain the title compound, yield 25.9% 〇Pale yellow needle-like crystals (chloroform-hexane)- 80- The paper standard (CNS) A4 specification (210X297 public director factory — ^ = ~ " — 1241295 A7 V. Description of the invention (77) Melting point: 130.2-131.2 ° C 1H-NMR (CDC13) 5: 1.33 (3Η, t, J = 7.1 Hz), 1.75 (3H, s), 1.87 (3H, s), 3.86 (3Η, s), 4.27 (2H, q, J-7.1 Hz), 4.84 (2H, d, J = 7.1 Hz), 5.41-5.50 (1H, m), 6.96 (2Η, d, J = 8.8 Hz), 7.78 (2H, d, J = 8.8 Hz), 8.09 (1H, b0, 8.23 (1H, s) 〇IR (KBr) cm i · 3216, 1722, 1644? 1605, 1539, 1518, 1255, 1176, 1027, 832. Mass spectrum (m / z): 357 (M +). Example 9 4'carboxy-2-ring Production of propylmethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-cyclopropylmethyl-6- (4-ethoxycarbonyl) -6- (4-methyl Oxyphenyl) -2H-pyridol-3-one was used as a raw material and treated in the same manner as in Example 86 to obtain the title compound in a yield of 99.7%. Melting point of yellow crystals: 153.9-154.7 ° C 1H-NMR (CDC13) δ: 0.050 · 66 (4Η, m), 1.41-1 · 51 (1Η, m), 3.88 (3Η, s), 4.23 (2Η, d, J = 7.3 Hz), 7.02 (2Η, d, J = 8.9 Hz), 7.81 (2H, d, J = 8.9 Hz), 8.64 (1H, s), 14.31 (1H, br). IRCKBi ^ cm · 1: 1743, 1630, 1608, 1558, 15 15, 1482, 1461, 1418. Example 9 5 2-Cyclopropylmethyl-4 · ethoxycarbonylamino-6- (4-methoxyphenyl) -2H-pyridazin-3-one-81-This paper is suitable for national standards of H (CNS) A4 specification (210 X 297 mm) 1241295 A7 p —_______ B7 V. Description of the invention (78) ~~ 一 ™ ~~~ * Manufactured one by one: 4_carboxy-2-cyclopropylmethylmethoxy Phenyl) -2H • pyridazine · 3_one was treated as in Example 87 to obtain the title compound in a yield of 44.2. / 〇. Color manipulation needle-like crystals (chloroform-hexane)

Melting point: 119.1-119.6 ° C 1H-NMR (CDC13) 5: 0.45_0-60 (4Η, m), 1.32-1 · 45 (4Η, m), 3.86 (3H, s), 4.11 ( 2Η, d, J = 7.3 Hz), 4 · 28 (2Η, q, J = 7.1 Hz), 6_96 (2H, d, J = 8.9 Hz), 7 · 79 (2Η, d, J = 8.9 Hz), 8.10 (1H, br), 8.25 (1H, s). IRCKBOcm-1: 3320, 1722, 1636, 1606, 1541, 1515, 1250, 1 178, 103 1, 1021, 887, 836 o Mass spectrum (m / z): 343 (M +). Example 9 6 Production of 2-fluorenyl-4 · carboxy-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-benzyl-4-ethoxycarbonyl-6- ( 4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 86 to obtain the title compound in a yield of 94.8%. Yellow crystal ^ -NMRCCDCls) 5: 3.88 (3Η, s), 5.50 (2Η, s), 7.01 (2Η, d, J = 8.8 Hz), 7.30-7.55 (5H, m), 7.81 (2H, d, J 8.8 Hz), 8.62 (1Η, s), 14_14 (1H, br). IR (KBr) cm · 1: 1750, 1633, 1607, 1516, 1472, 1457, 1419, 1250, 1026, 898, 838. Mass spectrum (m / z) 336 (M +). Example 9 7 82- This paper size applies Chinese National Standard (CNS) A4 specifications (210 x 297 public directors) 1241295 A7 B7 V. Description of the invention (^) a " ~~ — '土 4ethoxycarbonylamino group_ Production of 6- (4-methoxyphenyl) _2H-pyridazine-3 · pyridine: Mono-pyridyl-4_carboxy-6- (4 • methoxyphenyl) · 2Η • pyridazine_3 The ketone was used as the raw material, and treated in the same manner as in Example 87 to obtain the title compound in a yield of 11.20%. Α κ-color needle-like crystals (chloroform-ether) Melting point: 1 52.1- 162.5 ° C 1H-NMR (CDC13) 5: 1.33 (3Η, t, J = 7.1 Ηζ), 3.86 (3Η, s) , 4.25 (2Η, q, J = 7.1 Hz), 5.40 (2Η, s), 6.96 (2Η5 d, J = 8.9 Hz), 7.27-7.38 (3H, m), 7.45-7.50 ( 2H, m), 7.78 (2Η, d, J = 8.9 Hz), 8.07 (1H, brs), 8.24 (1Η5 s). IRCKBOcnT1: 3225, 1728, 1641, 1606, 1540, 1516, 1256, 1226, 1180, 1171, 829. Mass spectrum (m / z) · 379 (M +). Example 9 8 Production of 4-tetyl-6- (4-methoxyphenyl) -2- (3-phenylpropyl) -2H-pyridol-3-one: With 4-methoxycarbonyl-6- (4-methoxyphenyl) -2- (3-phenylpropyl) -2H-pyridazin-3-one was used as a raw material and treated in the same manner as in Example 86 to obtain the title compound in a yield of 85.8%. Light yellow needle-like crystals (chloroform-hexane) Melting point: 121.0-122.1 ° C ^ -NMRCCDCls) 5: 2.23 · 2 · 36 (2Η, m), 2.77 (2Η, t, J = 7.3 Ηζ), 3 88 (3Η, s), 4.41 (2H, t, J = 7.3 Hz), 7.01 (2H5 d, J = 8.8 Hz), 7.14-7 · 30 (5Η, m), 7.79 (2H, d, J = 8.8 Hz), 8.57 (1Η, s), 14.21 (1Η, br). -83- This paper size is in accordance with Chinese National Standard (CNS) A4 (210x 297 mm) 1241295 A7 V. Description of the invention (80) IRCKBOcm · 1: 1740, 1632, 1609, 1515, 1474, 1451, 1417, 1249 , 1187, 837. Example 9 9 Production of 4-ethoxycarboxyamino-6- (4-methoxyphenyl) -2- (3-phenylpropyl) -2H-pyridazin-3 · one: 4-carboxy-6 -(4-methoxyphenyl) _2- (3-phenylpropyl) -2） -pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 87 to obtain the title compound at a yield of 410.0 / 〇. Colorless needle-like crystals (chloroform-ether-hexane). Melting point: 100.9-101.3. (: ^ -NMRCCDCls) (5: 1.35 (3Η, t, J = 7.76Hz), 2.16-2 · 28 (2Η, m), 2.73 (2Η, t, J = 7.7 Hz), 3.86 (3Η, s), 4.28 (2Η, q, J = 7.1 Hz), 4.30 (2Η, t, J = 7.6 Hz), 6.96 (2H, d, J = 9.0 Hz), 7 · 14-7 · 31 (5Η, m), 7.77 (2Η, d, J = 9.0 Hz), 8.08 (1H, brs), 8.22 (1H, s). IRCKBOem · 1: 3223, 1725, 1641, 1608, 1547, 1517, 1225, 1200, 1175. Example 100 Production of 4_fluorenyloxycarbonyl-6 pneumomethoxyphenyl) -2_ (3_phenylpropyl) _2H-pyridazine_3_one : Using 4-carboxy-6- (4-methoxyphenyl) -2- (3-phenylpropyl) · 2Η-pyridazin-3-one as a raw material, treated as in Example 90 to obtain the title compound. The rate was 52.8 / 0.0. Needle-like crystals in typical colors (chloroform · hexane) Melting point: 117.6-118.TC (decomposition) 1H-NMR (CDC13) (5: -84- __ This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 (Mm) 1241295 A7 B7 V. Description of the invention (81) 2.15-2 · 27 (2Η, m), 2.72 (2H, t, J = 7_l Ηζ), 3.86 (3Η, s), 4.29 (2H, t , J = 7.1Hz), 5.23 (2H, s), 6.36 (2H, d, J = 8.9Hz), 7.13 · 7.30 (5H, m), 7.32 · 7.44 (5Η, m), 7.76 ( 2Η, d, J = 8.9 Hz), 8.16 (1H, brs), 8.22 (1H, s). IF ^ KBOcm · 1: 3221, 1733, 1640, 1604, 1539, 1516, 1500, 1252, 1220, 1175. Example 101 Production of 4-carboxy-2- (4-chlorocinnamyl) -6- (3,4-dimethoxyphenyl) -2H_pyridazin-3_one: 2- (4-chlorocinnamyl) Group) -6- (3,4-dimethoxyphenyl) _4-methoxycarboxyl_211-seuro-3 -one, treated as in Example 86 to obtain the title compound in a yield of 99.1%. Yellow fine needle-like crystals (chloroform-hexane) Melting point: 229.5-230.9 ° C (decomposition) 1H-NMR (CDC13) (5 · 3.95 (6Η, s), 5 · 11 (2Η, dd, J = 1) 〇, 6.8 Hz), 6.40 (1H, td, J = 6.8, 16.1 Hz), 6.75 (1H, td, J = 1.0, 16.1 Hz) , 6.97 (1H, d, J = 8.8 Hz), 7-33 (2H, d, J = 8.8 Hz), 7.39-7 · 45 (2Η, m), 8.67 (1H, s), 14.09 (1H, brs). N ^ KBOcnT1: 1753, 1635, 1570, 1520, 1471, 1460, 1238. Mass spectrum (m / z): 428 (M +), 426 (M +). Example 102 2- (4-Gas Cinnamonyl) -6- (3,4-dimethoxyphenyl) -4-ethoxycarbonylamido-2-pyridazine-3_one Manufacturing: -85- This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (82) 4_carboxy-2 · (4-chlorocinnamyl) _6- (3,4-dimethoxyphenyl) -2H-Da The azin-3-one was used as a raw material and treated in the same manner as in Example 87 to obtain the title compound in a yield of 43.6%. Slightly yellow needle-like crystals (chloroform-hexane). Melting point: 183.8-184.8 ° C ^ -NMRCCDCls) 5: 1 · 35 (3Η, t, J = 7.3 Hz), 3.93 (3H, s), 3.94 (3Η, s), 4.29 (2Η, q5 J = 7.3 Hz), 5.01 (2H, dd, J = 1.0, 6 · 6 Hz), 6.41 (1H, td, J = 6.3, 15.8 Hz), 6.65 (1H, dt, J = 15.8, 1.0 Hz), 6.92 (1Η, d, J = 8.2 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.31 (2Η, d, J = 8.6 Hz), 7.37 (1Η, dd5 J = 2.2, 8.2 Hz), 7.42 (1Η, d, J = 2.0 H z), 8.09 (1Η, br), 8.27 (1H, s). IR (KBr) cm · 1: 3232, 3023, 1725, 1636, 1607, 1544, 1519, 1491, 1423, 1262, 1223, 1 151, 1022. Mass spectrum (m / z): 471 (M +), 469 (M +). Example 103 Production of 4-¾yl-2- (4-aminocinnamoyl) -6- (3-murine-4-methoxyphenyl) -211-stitching-3-isocyanate: 2- (4 -Chlorocinnamyl) -6- (3-chloro-4-methoxyphenyl) -4-methoxycarbonyl-2H-pyridazin-3-one as a raw material, the same treatment as in Example 86 was carried out to obtain the title compound. The rate is 96.5%. Light yellow fine needle-like crystals (chloroform-Kiyuan) Melting point: 215.8-219.2 ° C ^ -NMRCCDCls) ^: -86- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 ^ ___ B7 V. Description of the invention (83) 3.97 (3Η, s), 5.10 (2H, dd, J2 1.5, 6 · 8 Hz), 6.39 (1Η, td, J2 6.8, 16.1 Ηζ ), 6.75 (1Η, td, J = 1.5, 16.1 Ηζ), 7.03-7.10 (1Η, m), 7.30 (2Η, d, J = 9.0 Ηζ), 7.33 (2Η, d , J 2 9.0 Ηζ), 7.54 · 7.59 (1Η, m), 7.66-7 · 72 (1Η, m), 8.61 (1Η, s), 13.99 (1Η, br) ο IRCKBOcriT1: 1745, 1628 , 1523, 1481, 1437, 1271. Mass spectrum (m / z): 416 (M +), 414 (M +). Example 104 Production of 2- (4-chlorocinnamyl) -4-ethoxycarbonylamino-6- (3-fluoro-4-methoxyphenyl) -2Η-pyridazin-3-one: 4- Carboxyl-2- (4-chlorocinnamyl) _6- (3-fluoro-4-methoxyphenyl) -2'-pyridazine 3-ketone was used as a raw material, and treated in the same manner as in Example 87 to obtain the title compound. The rate is 29.4%. Light yellow fine needle-like crystals (chloroform-hexane) Melting point: 186.7-187.5 ° C 1H-NMR (CDC13) δ: 1.35 (3Η, t, J = 7.1 Ηζ), 3.94 (3Η, s), 4.29 (2H, q, J = 7.1 Ηζ), 4.99 (2Η, dd, J = 1.2, 6.6 Hz), 6.39 (1Η, td, J = 6.6, 16.1 Hz), 6.65 (1H, td, J = 1.2, 16.1 Hz), 6.97-7 · 04 (1Η, m), 7.27 (2H, d, J = 8.8Hz), 7.30 (2H, d, J = 8.8Hz), 7.51-7.56 (lH, m), 7.62-7.68 (1H, m), 8.08 (1H, brs), 8.24 (1H, s). IRCKBiOcnT1 · 3217, 1728, 1644, 1610, 1544, 1520. Mass spectrum (m / z): 459 (M +), 457 (M +). Example 10 5 -87- This standard is applicable to the Chinese National Standard (CNS) A4 specification (21 × 297, 1241295 A.7 B7) V. Description of the invention (84) ------- '1- 4-1 base- Production of 2- (4-chlorocinnamyl χ_ (3-fluoro + methoxyphenyl) _2h_pyridazinone): 2 (4-chlorocinnamyl) _6_ (3_fluoro-4_methoxyphenyl) 'Methoxycarbonyl-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 86 to obtain the title compound with a yield of 95.1%. Light mechanically crystalline powder (chloroform-hexane) ^ -NMRiCDCls) δ: 3_98 (3H, s), 5.11 (2Η, dd, J = 1.0, 6.8 Hz), 6.39 (1H, td, J-6.8, 15.6 Hz), 6.76 (1Η, td, J = 1. 〇, 15.6 Hz), 7.03 (1Η, d, J-8.6 Hz), 7.30 (2Η, d, J = 8.8 Hz), 7.33 (2H, d, Bu 8.8 Hz), 7.71 (1Η , Dd, J = 2.1, 8.6 Hz), 7.96 (1Η, d, J = 2.1 Hz), 8.63 (1H, s), 13.99 (1H, br) 〇IR (KBr) cm 1 · 1748, 1628, 1508, 1481, 1407, 1292, 1260. Mass spectrum (m / z): 432 (M +), 430CM +). Example 106 2- (4-chlorocinnamyl) -6- (3-chloro-4-methoxybenzene ) -4-Ethoxycarbonylamido-2H-pyridazin-3-one production: 4_Ethyl-2_ (4-chlorocinnamyl) _6- (3- -4 -methoxyphenyl) -2H-pyrazine · 3-ketone as a raw material, treated in the same manner as in Example 87 to obtain the title compound in 44.9% yield. Colorless fine needle-like crystals (chloroform-hexane). Melting point · 183.0-183.8 ° C 1H-NMR (CDC13) 5: 1.35 (3H, t, J = 7.1 Hz), 3.95 (3Η, s), 4.29 (2H, q5 J = 7_l Hz), -88- ^ The scale is applicable to China National Standard (CNS) A4 specification (210 x 297 mm ^ 1241295 A7 B7 V. Description of the invention (85) 4 · 99 (2Η, dd, J 2 1.0, 6 · 6 Ηζ), 6.40 (1Η, td, J = 6.6, 15.8 Hz), 6.66 (1Η, dt, J = 15.8, 1.0 Hz), 6.97 (1H, d5 J = 8.6 Hz), 7.27 (2H, d, J = 8.7 Hz ), 7.31 (2Η, d, J = 8.7 Hz), 7.69 (1H, dd, J = 2.3, 8.6 Hz), 7.91 (1H, d, J = 2.3 Hz), 8.09 (1H, brs), 8.24 (1H5 s). IR (KBr) cm · 1: 3235, 1724, 1641, 1606, 1540, 1508, 1264, 1229. Mass spectrum (m / z): 475 (M +), 473 (M +). Example 107 Production of 4-carboxy-2- (4-chlorocinnamyl) -6- [4- (methylthio) phenyl] -2H-pyridazin-3-one: 2- (4-chlorocinnamyl Group) -4-methoxycarbonyl-6- [4- (methylthio) phenyl] -2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 86 to obtain the title compound, yield 77.1% . Yellow prism (chloroform-hexane) Melting point: 176.0-177.6 ° C (decomposed) lU ^ MR (COCU) δ: 2.54 (3H, s), 5.11 (2H, d, J = 6.8 Hz), 6.39 (1H, td, J = 6_8, 15.9 Hz), 6.74 (1Η, d, J = 15.9 Hz), 7.25-7.37 (6H, m), 7.78 (2H, d, J = 8.8 Hz), 8.66 (1Η , S), 14.01 (1H, br). IRCKBOcnT1: 1749, 1655, 1630, 1594, 1567, 1492, 1474, 1403. Mass spectrum (m / z): 414 (M +), 414 (M +). Implementation Example 10 8 -89- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7

Production of 2- (4-chlorocinnamyl) · cardiethoxycarbonylamino (methylthio) phenyl] _2H_pyridol 3-ketone: * _ with 4_imidyl_2- (4-chlorocinnamyl ) -6- [4- (methylthio) phenyl] -2H-pyridine was used as the starting material 'and treated as in Example 87 to obtain the title compound in a yield of 13.6%. Slightly yellow fine needle-like crystals (chloroform_hexane). Melting point: 158.3-162.1. (: 'H.NMRiCDC ^) ^: 1.35 (3Η, t, J = 7.1 Ηζ), 2.52 (3Η, s), 4.29 (2Η, q, J = 7.1 Hz), 5 · 00 (2Η, dd, J = 1 ", 6.5 Hz), 6.40 (1Η, td, J = 6.5, 15.9 Hz), 6.65 (1H, td, J = 11, 15.9 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.7 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.76 (276, d, J = 8.7 Hz), 8.13 (1H, br), 8.27 (1H, s). IRCKBOcm · 1: 3220, 1728, 1641, 1606, 1538, 1501, 1491. Mass spectrum (m / z): 457 (M +), 455 (M +). Example 109 Production of 4-carboxy-2- (2,4-difluorocinnamyl) -6- (4-methoxyphenyl) -2H-serazin-3-one: 2- (2,4- Difluorocinnamoyl) -4-methoxycarbonyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 86 to obtain the title compound. Yield: 93.1% . Light yellowish fine needle-like crystals (chloroform-hexane) Melting point: 200.3-201.3 ° C ^ -NMRCCDCls) 5: -90- This paper size applies to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 _______________ B7 — ~~ r ~~ — ~~ — ............. 3.88 (3H, s), 5.11 (2Η, dd, J = 1.2, 6.8 Hz), 6.45 (1H, td, J = 6.8, 16.1 Hz), 6.73-6.92 (3H, m), 7.01 (2H, d, J = 8.8 Hz), 7.37-7 · 48 (1Η, m), 7.82 (2Η, d, Bu 8.8 Hz), 8.66 (1H, s), 14.09 (1Η, brs). IR (KBr) cmi 3065, 1741, 1632, 1608, 1504, 1474, 1419, 1252, 967. Mass spectrum (m / z): 398 (M +). Example 110 Production of 2- (2,4-difluorocinnamyl) -4-ethoxycarbonylamino-6- (4-methoxyphenyl) -2H-pyridoxan-3-one: 4-thin 2- (2,4-difluorocinnamyl) · 6- (4-methoxyphenyl) _2Η · pyridazin-3-one as a raw material, treated as in Example 87 to obtain the title compound, yield 30.0 / 0. Light yellow microneedle crystal (chloroform-hexane) Melting point: 128.3-128.9 ° C ^ -NMRCCDCls) 5 · 31 · 5 (3Η, t, J = 7.1 Ηζ), 3.86 (3Η, s), 4.28 ( 2H, q, J = 7.1 Hz), 5.01 (2H, dd, J = 1.2, 6.6Hz), 6.44 (lH, td, J = 6.6, 16.1Hz), 6.73-6.86 (3H, m), 6.96 (2H , D, J = 8.8 Hz), 7.36-7 · 46 (1Η, m), 7.79 (2H, d, J = 8.8 Hz), 8.08 (1Η, brs), 8.26 (1H, s). IRCKBOcnT1: 3221, 3073, 1728, 1641, 1605, 1541, 1519, 1502, 1256, 1224, 1176. Mass spectrum (m / z): 398 (M +). Example 111 Preparation of 4-amino-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazin-3-one-91-_______________ This paper size applies to Chinese national standards (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (88 products: based on 2- (4-chlorocinnamyl) -4-ethoxycarbonylamino-6- (4-methoxybenzene Base)-2H_sulpyrazin-3-one 335 mg (0.76 mmol) in a suspension of methanol (40 ml) was added with 20 ml of 4N NaOH aqueous solution, stirred at 70 for 30 minutes, methanol was distilled off, and the residue Add 100 ml of water, extract with chloroform, wash the organic layer with saturated brine, and dry over anhydrous NajCU. The solvent was distilled off, and the resulting residue was separated and purified by silica gel column chromatography (silica gel 10 g, chloroform). Crystallization from chloroform-hexane gave colorless fine needle crystals to obtain 266 mg (95.0%) of the title compound.

Melting point: 142.7-143.2 ° C 1h ^ mr (coc \ 3) δ: 3.84 (3Η, s), 4.93-5 · 01 (4Η, m), 6.43 (1H, td, J = 6.4, 15.9 Ηζ), 6.64 (1Η, td, J = 1.0, 15.9 Hz), 6.69 (1Η, s), 6.95 (2H, d, J = 8.9 Hz), 7.25 (2Η, d, J = 8.6 Hz), 7.31 (2Η, d5, 8.6 Hz), 7.69 (2Η, d, J = 8.9 Hz). IR (KBr) cm'1: 3435? 3325, 3038? 1646, 1612, 1597, 1521, 1491, 1252, 1238, 833. Mass spectrum (m / z). 369 (M +), 367 (M +). Example 112 Production of 2- (4-chlorocinnamyl) -4-carboxamido-6- (4-methoxyphenyl) -2H-pyridazin-3-one: Based on 4-amino-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazin-3 -one 40 mg (0.11 mmol) in benzene (2 ml) solution was added with 151 mg of triethylamine ( 1.49 mmol) and 0.5 ml of a mixture of formic acid and acetic acid (1: 1) was stirred at room temperature for 16 hours. The reaction solution was extracted with chloroform, and saturated NaHC03 aqueous solution, saturated -92-this paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (89) and the order of saline solution After cleaning, it was dried over anhydrous NajO4. The solvent was removed, and the obtained residue was crystallized from chloroform-hexane to obtain 41 ml (95.2%) of the title compound as colorless needle crystals. Melting point: 213.0-213.8 ° C ^ -NMRCCDCls) 5: 3.86 (3H, s), 5.0 (2Η, dd, J = 1.0, 6 · 5 Ηζ), 6.40 (1Η, td, J-6.5, 15 · 9 Hz), 6.66 (1Η, td, J = 1.0, 15.9 Hz), 6.97 (2Η, d, J = 9.0 Hz), 7.26 (2H, d, J = 8.8 Hz), 7.32 ( 2H, d, J = 8.8 Hz), 7.79 (2H, d, J = 9.0 Hz), 8.59 (1H, s), 8.64 (1Η, s), 8.79 (1H, br) o IR ^ KBOcm · 1 : 3277, 1702, 1634, 1601, 1549, 1518, 1491, 1418, 1245, 1 138, 1033, 812. Mass spectrum (m / z): 397 (M +), 395 (M +). Example 113 4-Ethylamine- 2- (4-murinyl) -6- (4-methoxyphenyl) _211-stitching-3_

To 4-amino-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazine_3-pyrene and 40 mg (0.11 mol) of anhydrous acetic acid 0.5 Ml, heated at 70 ° C for 12 hours. A saturated NaHC03 aqueous solution was added to the reaction solution, and the mixture was stirred at room temperature for j hours, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous NajCU. The solvent was distilled off, and the obtained residue was separated and purified by silica gel fractionation chromatography (developing solvent: hexane / ethyl acetate (1/1)), and then crystallized from chloroform and hexane to obtain the title compound 3 1 Mg (70.0%) was light brown needle-like crystals. Melting point: 158.7-161.9 ° C -93- The size of this paper applies to Chinese National Standard (CNS) A4 (210X 297 mm) 1241295 A7 B7 V. Description of the invention (9〇) 1u ^ mr (coc \ 3) δ · 2 · 27 (3Η, s), 3.86 (3Η, s), 5.00 (2Η, dd, J 1.2, 6.4 Ηζ), 6.39 (1Η, td, J 2: 6.5, 15.9 Ηζ) , 6.65 (1Η, td, J = 1.2, 15.9 Ηζ), 6.97 (2Η, d, Bu 9.0 Ηζ), 7.27 (2Η, d5 J = 8.9 Ηζ), 7_30 (2Η, d, J = 8.9 Hz), 7.79 (2Η, d, J = 9.0 Ηζ), 8.58 (1Η, s), 8.61 (1Η, brs). IRCKBOcnT1: 3274, 3002, 17015 1634, 1 603, 1537, 1 5 16, 1491, 1405, 1252, 1180, 1070. Mass spectrum (m / z): 411 (M +), 409 (M +). Example 114 Production of 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4-propanamido-2H-pyridazin-3-one: 4-Amino-2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) _2H-pyridazin-3-one and anhydrous propionic acid were treated in the same manner as in Example 113 to give the title compound in a yield of 84.6%. Colorless needle-like crystals (chloroform-hexane) Melting point: 147.7-148.6 ° C lH ^ UR (COC \ 3) δ: 1.26 (3Η, t, J = 7.6 Hz), 2.51 (2H, q, J = 7.6 Hz), 3.86 (3H, s), 5.0 (2Η, dd, J = 1.2, 6 · 4 Ηζ), 6.40 (1Η, td, J = 6.4, 15.9 Ηζ), 6.65 (1Η, td, J = 1.2, 15 · 9 Ηζ), 6.96 (2Η, d, J = 9.0 Ηζ), 7.27 (2Η, d5 J = 8.8 Hz), 7.30 (2Η, d, J = 8.8 Ηζ), 7.79 (2Η , D, J = 9.0 Ηζ), 8.61 (1Η, brs), 8.62 (1Η, s). IRCKBOcm · 1: 3270, 3046, 1633, 1599, 1534, 1516, 1492, 1255, 1 173, 833, 772. I Lu This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (91) Mass spectrum (m / z) ·· 425 (M +), 423 (M +). Example 115 Production of 4-n-butylamino-2- (4-chlorocinnamyl) -6_ (4-methoxyphenyl) -2H-pyridazin-3-one: 4-amino-2- ( 4-chlorocinnamyl) -6- (4-methoxyphenyl) -2H-pyridazin-3-one and anhydrous butyric acid were treated in the same manner as in Example 113 to obtain the title compound in a yield of 88.2%. Colorless needle-like crystals (chloroform-hexane) Melting point: 152.1-152.7 ° C ln-NMR (COC \ 3) δ · 1.04 (3Η, t, J = 7.5 Ηζ), 1.70-1 · 85 (2Η , M), 2.45 (2Η, t, J = 7.3 Hz), 3.86 (3Η, s), 5.00 (2Η, dd, J = 1.2, 6.4 Hz), 6.41 (1Η, td , J = 6.4, 15.9 Hz), 6.64 (1H, td, J = 1.25 15.9 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.27 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.8 Hz), 7.79 (2H, d, J: 8.9 Hz), 8.60 (1H, brs), 8.62 (1H, s). n ^ KBOcriT1: 3271, 305 1, 3034, 1632, 1598, 1532, 1517, 1500, 1258, 1172. Mass spectrum (m / z): 439 (M +), 437 (M +). Example 114 Production of 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4- (N-methylethoxycarbonylamino) -2H-pyridazin_3_one: 100 ¾ grams of 2- (4-chlorocinnamyl) -4-ethoxyamido-6- (4-methoxyphenyl) -211-stitching 3-ketone in the presence of methyl moth and bell carbonate, It was stirred in N, N-dimethylformamide at 80 C for 1 hour, and treated in the same manner as in Example 1 to obtain 92 mg (89.2%) of the title compound. This paper size applies to China National Standard (CNS) A4 (210 X 297 male) 1241295

Slightly yellow fine needle-like crystals (chloroform-hexane) Melting point: 130.8-131.51 ^ -NMRCCDCls) 5: 1.27 (3Η, t, J = 7.1 Ηζ), 3.30 (3Η, s), 3_86 (3H, s), 4.22 (2Η, q, J = 7.1 Hz), 5.00 (2Η, dd, J = 1.〇, 6.3 Hz), 6.42 (1Η, td, J = 6.6, 15.9 Hz) , 6.67 (1H, td, J = 1.05 15.9 Hz), 6.97 (2H, d, J = 9.0 Hz), 7.27 (2Η, d, Bu 8.7 Hz), 7.31 (2Η, d, J = 8.7 Hz), 7.63 (1H, s), 7.71 (2H, d, J = 9.0 Hz). n ^ KBOcm · 1: 17〇6, 1655, 1611, 1520, 1316, 1307, 1252, 1176. Mass spectrum (m / z): 455 (M +), 453 (M +). Example 117 Production of 2- (4-chlorocinnamyl) -6_ (4-methoxyphenyl) -4-methylamino-2H-pyridazinone: 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4- (N-methylethoxycarbonylamino) _ 2H-pyridazin-3-one 68 mg as a raw material, the same as in the example (stirred at 70 ° C), when ) To give 49 mg (93.9%) of the title compound. Colorless needle-like crystals (chloroform-hexane) Melting point: 148.4-149.2 ° C 1H-NMR (CDC13) 5 · 2.96 (3Η, d, J = 5.1 Ηζ), 3.85 (3Η, s), 4.96 ( 2H, dd, J spit 2, 6 4 Hz), 5.77 (2H5 brq, J = 5.1 Hz), 6.33 (1Η, s), 6.42 (1H, td, J = 6.4? 15.9 Hz) 9 6.62 (1H5 td5 J = 1.2, 15.9 Hz), 6.96 (2H d J = 9.0 Hz), 7.25 (2H, d, J = 8.9 Hz), 7 · 30 (2Η, d, J = 8.9 Hz) -96- paper size Applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1241295 A7 _ B7 V. Description of the invention () 7 · 7 4 (2 Η, d, J: 9 · Ο Η z). IR ^ KBiOcm-1: 3318, 1630, 1606, 1519, 1432, 1240. Mass spectrum (m / z): 383 (M +), 381 (M +). Example 11 8 2- (4-chlorocinnamyl) _6 · (4-methoxyphenyl) -4_ [N- (3-phenylpropyl) ethoxycarbonylamino] -2Η-pyridazin_3_one Manufactured from: 2- (4-chlorocinnamyl) _4-ethoxycarbonylamino-6-4-methoxyphenyl) -2Η-pyridazin-3-one and 70 mg of 3-phenylpropyl bromide In the same manner as in Example η6, 1 g of the title compound 61 (68.7%) was obtained. Colorless fine needle-like crystals (chloroform-ether-hexane) Melting point: 113.5-114.2 ° C 1H-NMR (CDC13) (5: 1.22 (3Η, t, J = 7.1 Ηζ), 1.85-1 · 98 (2Η, m), 2.65 (2Η, t, J = 7.7 Hz), 3.79 (2Η, t, J = 7.4 Hz), 3.86 (3H, s), 4.19 (2H, q, J = 7.1 Hz), 4.99 (2H, dd, J = 1.0, 6.3 Hz), 6.42 (1H, td, 15.9 Hz), 6.65 (1Η, td, J = 1.0, 15.9 Hz), 6.97 (2H , D, J = 8.8 Hz), 7.27 (2H, d, J = 8.9 Hz), 7.10-7.33 (9H, m), 7.48 (1H, s), 7.68 (2H, d, J = 8.8 Hz). IR (KBr) cm · 1: 1678, 1657, 1616, 1522, 1305, 1252, 1183, 1166. Mass spectrum (m / z): 559 (M +), 557 (M +). Example 119 2- (4-chlorocinnamon Based) -6- (4 -methoxyphenyl) -4- (3-phenylpropyl) amino-3 -one: -97-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7

With 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) _4- [N- (3-phenylpropyl) ethoxycarbonylamino] -2H-pyridazin-3-one 3 1 Mg was used as a raw material, and treated in the same manner as in Example 1 to obtain 26 mg (96-3%) of the title compound. Colorless fine needle-like crystals (chloroform-hexane) Melting point: 161.2-162.6t: ^ -NMRCCDCls) (5: 1.96-2 · 09 (2Η, m), 2.76 (2Η, t, J = 7.4 Hz) ), 3.17-3.26 (2H, m), 3.85 (3H, s), 4.96 (2H, dd5 J = 1.2, 6.4 Hz), 5.79 (1H, brt, J = 5.5 Hz), 6.25 (1H, s), 6.43 (1H, td, J = 6.4, 15.9 Hz), 6.63 (1H, td, J = 1.2, 15.9 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.17-7.34 (9H, m), 7.68 (2H, d, J = 8.9 Hz). IRCKBi ^ cm'1: 3315, 1630, 1602, 1519, 1258, 1 177, 821. Mass spectrum (m / z): 487 (M +), 485 (M +). Implementation Example 120 2- (4-chlorocinnamyl) -6- (4-methoxyphenyl) -4- [N- (2.pyridylmethyl) ethoxycarbonylamino] -2Η-pyridazin-3-one Production: 70 mg of 2- (4-chlorocinnamyl) -4-ethoxycarbonylamino-6- (4-methoxyphenyl) _211-pyridazin-3-one is the same as 2-pyridylmethyl bromide Treatment of Example 116 (stirring at 70 ° C. for 4 hours) yielded 82 mg (97.0%) of the title compound. 1H-NMR (CDC13) δ light brown oil: 1.18 (3Η, t, 7.1 7.1ζ) , 3.85 (3Η, s), 4.20 (2H, q, J = 7.1 Ηζ), 4.98 (2H, dd, J = 1.05 6.3 Hz), 5.05 (2Η, s), 6.40 (1Η, td, J = 6.6, 15 · 9 Hz), 6.63 (1H, td, J = 1.0, 15.9 Hz), 6.95 (2H, d5 -98-This paper size applies to China National Standard (CNS) A4 (210x297 mm) 1241295 A7 B7 V. Description of the invention (95) J 2: 8 · 8 Ηζ), 7.11-7.17 (1Η, m), 7.27 (2Η, d, J 2 9.0 Hz), 7.29 (2H, d, J = 9.0 Hz), 7.40-7.45 (lH, m), 7.59-7 · 64 (1Η, m), 7.67 (2Η, d, J = 8.8 Hz), 7.78 (1Η, s), 8.49-8.53 (1H, m). IR (thin film km · 1 ·· 1716, 1660, 1652, 1610, 1519, 1305, 1252, 1209, 1169. Mass spectrum (m / z): 532 (M +), 530 (M +). The hydrochloride salt of one of the title compounds was obtained according to customary usage with a yield of 74.2%. Light brown amorphous crystal Melting point: 90 ° C (softened) ^ -NMRCCDCls) 5: 1.16 (3Η, t, J = 7.1 Ηζ), 3.85 (3Η, s), 4.17 (2Η, q , J = 7.1 Hz), 5,05 (2H, dd, J = 1.0, 6.4 Hz), 5.09 (2H, s), 6.48 (1H, td, J = 6.4, 15.9 Hz), 6.69 (1H, td, J = 1.0, 15.9 Hz) 5 7.03 (2H, d, J = 8.8 Hz), 7.30 (2H, d, J = 8.5 Hz), 7.40 (2H, d, J = 8.5 Hz), 7 · 72-7 · 79 (1Η, m), 7.83 (2H, d, J = 8.8 Hz), 7.97-8.03 (1H, m), 8.16 (1H, s), 8.27-8 · 36 (1Η, m ), 8.69-8.74 (1H, m). IR (KBr) cm'1: 17175 1652, 1570, 1519, 1305, 1251, 1225, 1169. Example 121 Production of 4-amino-2-cetyl-6- (4-methoxyphenyl) -2H-pyridazin-3-fluorene: 2-fluorenyl-4-ethoxycarbonylamino-6- (4-methoxyphenyl) · 2'-pyridazin-3-one as a raw material was treated in the same manner as in Example 111 to obtain the title compound in a yield of 57.4%. Light brown prisms (chloroform-hexane)

Melting point: 115.1-115.6 ° C -99- The paper size is applicable to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1241295 A7 B7 V. Description of the invention (96) ^ -NMRCCDC ^) (?: 3.85 (3Η, s), 4.94 (2H, br), 5.39 (2 (, s), 6.95 (2Η, d, J = 8.8 Hz), 7.24-7 · 37 (3 ·, m), 7 · 47-7 · 52 (2Η, m), 7.69 (2Η, d, J = 8.8 Hz) IRCKBrOcnT1 · 3419, 3322, 3286, 3259, 1644, 1600, 1519, 1251, 1184, 1021, 839 〇 Mass spectrum (m / z): 307 (M +). Example 122 Production of 2-benzyl-4-methanesulfonamido-6- (4-methoxyphenyl) -2H-pyridazin-3 -one : (1) Production of 2 • benzyl-4_methanesulfonamido · 6 · (4-methoxyphenyl) -2H-pyridazin-3-one: Based on 4-amino-2-benzyl- 60-grams (0.20 mmol) of 6- (4-methoxyphenyl) _2H-pyridazin-3-one and toluene (1 ml) of 80 mg (0.079 mmol) of triethylamine in Add 70 mg (0.61 mmol) of mesylmethane chloride, and stir at 40.0! Hours. Add chloroform to the reaction solution, wash the organic layer with water and saturated brine, and dry under reduced pressure to distill off. Solvent, the resulting residue was subjected to silica gel chromatography ( Solvent: hexane / ethyl acetate (1/1) was separated and purified to obtain the title compound 76 mg (90.4%). LH-NMR (CDCl3) (5: 3.55 (6H, s), 3.86 (3H, s) , 5.43 (2Η, s) 5 6.70 (2H, d, Bu 9.2 Hz) 7.27-7_37 (3H5 m), 7.42-7_46 (2Η, m), 7.65.7 · 7〇 (3m, m) ％ (2) Production of 2-benzyl-4-methanesulfonamido-6_ (4_methoxyphenyl) _2H_pyridazinone: -100-

1241295 A7 B7 V. Description of the invention (97 in 2-fluorenyl-4-dimethylsulfonamido-6- (4-methoxyphenylb 2H-pyridazinone) 36 亳 g (0.08 mmol) methanol (1 ml), add 1 ml of 4N NaOH aqueous solution, and stir at room temperature for 2 hours. Make it acidic with hydrochloric acid under ice-water cooling, add 30 ml of water, and extract with chloroform (20 （L x 2). The organic layer was washed with saturated brine, and then dried over anhydrous NkSCU. The solvent was distilled off under reduced pressure, and 31 mg of the resulting residue was crystallized from chloroform-hexane to obtain 2 6 g (86.9%) of the title compound as a fine. Brown needle-like crystals. Melting point: 195.0-195.5 ° C lH ^ MR (COC \ 3) δ: 3.13 (3Η, s), 3.86 (3Η, s), 5.40 (2Η, s), 6 · 98 (2Η, d, J = 8.8 Hz), 7.30 · 7 · 39 (3Η, m), 7.47-7 · 51 (2Η, m), 7.75 (2Η, d, J = 8.8 Hz) , 8.02 (1Η, br). IRCKBOcnT1: 3151, 1634, 1599, 1440, 1250, 1154, 1021, 835, 770, 753, 700. Mass spectrum (m / z) · 385 (M +). Example 123 Production of 2-fluorenyl-4- (3-isopropylureido) -6- (4-methoxyphenyl) -2H-pyridazin-3-one: In 4-amino-2-benzyl-6 -(4-methoxyphenyl) _2H_Da To a solution of _3_ketone 50 mg (0.16 mmol) in benzene (2 ml) was added isopropyl isocyanate (0.0 ml) (1.02 mmol) and stirred at 60 ° C for 17 hours. Distilled off Solvent, the obtained residue was separated and purified by silica gel chromatography (developing solvent: chloroform / methanol (15/1), and 63 mg of the obtained crude crystals were recrystallized from chloroform-hexane to obtain 56 mg of the title compound, ( 87.7%) are colorless needle-like crystals. -101-This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 male I) 1241295 A7 B7 V. Description of the invention (98) Melting point: 200.2-201.0 ° C ^- NMRCCDCls) δ · 1.15 (3Η, s), 1.18 (3Η, s), 3.85 (3Η, s), 3.92-4.07 (1H, m), 5.38-5 · 52 (3Η, m), 6.93 (2Η, d, J = 8.9 Ηζ), 7.25-7 · 45 (5Η, m), 7.79 (2Η, d, J = 8.9 Ηζ), 8.31 (1Η, brs), 8 47 (1Η, s) IR (KBr) cm-1 · 3370, 3283, 1698, 1624, 1592, 1517, 1255, 1175, 1032, 830, 701. Mass spectrum (m / z): 392 (M +). Example 124 Production of 4-amino-2-cyclopropylmethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one: 2-cyclopropylmethyl-4-ethoxycarbonyl Amino-6- (4-methoxyphenyl) -2H-pyridazin-3-one was used as a raw material, and treated in the same manner as in Example 111 (40 minutes at 60 minutes) to obtain 82 mg (97.0%) of the title compound. ). Colorless needle-like crystals (chloroform-hexane)

Melting point: 110.8-111.3 ° C 1H-NMR (CDC13) 5: 0.44--0.59 (4Η, m), 1.35-1.52 (1Η, m), 3.85 (3Η, s), 4.09 (2H, d, J = 7.3 Hz), 4.95 (2Η, b〇, 6.68 (1Η, s), 6.95 (2Η, d, J = 8.9 Hz), 7.70 (2H, d, J = 8.9 Hz). IK ^ KBOcnT1: 3455, 3300, 3261, 3206, 1641, 1601, 1575, 1520, 1420, 1246, 1239, 1025, 835. Mass spectrum (m / z): 271 (M +). Examples 125 2-Cyclopropylmethyl-4- (3-isopropylureido) -6- (4-methoxyphenyl) -2H-pyridazin-3-one-102- This paper size applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1241295 A.7

B7 Production: Using 4-amino-2-cyclopropylmethyl-6- (4-methoxyphenyl) -2H-pyridazin-3-one as a raw material, the same treatment as in Example 123 was performed to obtain the title compound. The rate was 77.00 //. Colorless needle-like crystals (chloroform-hexane) Melting point: 195.8-197.0 ° C 1H-NMR (CDC13) 5: 0.45-0 · 62 (4Η, m), 1.24 (3Η, s), 1 · 27 (3Η, s), 1.34-1.51 (1H, m), 3.85 (3Η, s), 4.00-4 · 15 (3Η, m), 5.85 (1H, brd, J = 7.9 Hz), 6.95 (2H, d, J = 8.9 Hz), 7.81 (2H, d, J = 8.9 Hz), 8.53 (1 (, s), 8.55 (1H, brs). IR (KBr) cm 1: 3324, 1694, 1622, 1611, 1591, 1538, 1516, 1253, 1 175, 1033, 836. Mass spectrum (m / z): 356 (M +). Example 126 Production of 2-cyclopropylmethyl-4-methanesulfonamido-6- (4-fluorenoxyphenyl) _2H_pyridazinone: (1) 2-cyclopropylmethyl-4-dimethyl Production of sulfanilino-6- (4-methoxyphenyl) _2H-pyridin-3-one: 4-amino-2-cyclopropanyl-6- (4-methoxyphenyl) > 211_pyridazinone was used as a raw material, and treated in the same manner as in Example 122- (1) to obtain the title compound in a yield of 90.1%. 1H-NMR (CDC13) 5: 0.43-0 · 63 (4Η, m) , 1.33-1.49 (1H, m), 3.57 (6H, s), 3.87 (3H, s), 4.13 (2H, d, J-7.3 Hz), 6.99 (2Η, d, J = 8.6 Hz), 7 · 71 (2Η, d, J = 8.6 Hz), 7 · 72 (1Η, s). -103- ___________ This paper size is applicable to China National Standard (CNS) A4 (210 x 297 mm) 1241295 A7 B7 5 Description of the invention ((2) Production of 2-cyclopropylmethyl-4-methylsulfonamido-6- (4-methoxyphenyl) _2H-pyridazin-3-one: 2 · cyclopropylmethyl_ 4-Methanesulfonylamino-6- (4-methoxyphenyl) -2H-pyridazin-3-pyrene was used as the starting material and treated in the same manner as in Example 122_ (2) to obtain the title compound in a yield of 81.0% 〇Colorless needle-like crystals (chloroform-hexane)

Melting point: 203.3-203.9 ° C 1H-NMR (CDC13) 5: 0.45 ·· 63 (4Η5 m), 1.35 · 1 · 50 (1Η, m), 3.16 (3Η, s) 5 3.87 (3Η, s), 4.12 (2Η, d, J = 7.3 Ηζ), 6.98 (2Η, d, J = 8.8 Ηζ), 7.74 (1Η, s), 7.75 ( 2Η, d, J = 8.8Ηζ), 8.09 (1Η, br). IR (KBr) cm_1: 3124, 1641, 1604, 1583, 1517, 1448, 1347, 1253, 1 148, 1025, 864, 833. Mass spectrum (m / z): 349 (M +). Example 127

Production of 4-Aminomethyl-6- (3-chloro-4-fluorophenyl) -2-cinnamyl-2H-pyridazin-3-one: 6- (3-chloro-4-fluorophenyl ) -2-Cinnamyl-4-ethoxycarbonyl-2H-pyridazin-3-one as a raw material, treated in the same manner as in Example 38 to obtain the title compound in a yield of 64.8%. Light yellow needle-like crystals (methanol) Melting point: 211.0-212.0 ° C lH-NMR (CDCl3) 5: 5 „05 (2H, d, J = 5.9 Hz), 6.52 (1Η, td, J = 5.9, 15 · 8 Ηζ), 6.68 (1H, d, J = 15.8 Hz), 7.22-7 · 38 (3Η, m), 7.47 (2H, d, J = 6.9 104)-This paper standard applies to Chinese national standards (CNS) A4 specifications (210X297 male) 1241295 A7 B7 Five invention descriptions (101) _ ~~~~~ " " "

Hz), 7.55 (1H, t, J = 8.9 Hz), 7.95-8.02 (1H, m), 7.08-8.20 (2H, m), 8.59 (1H, s), 8.82 (1H, brs). IR (KBr) cm_1: 3306, 3135, 1705, 1632, 1578, 1506, 1407, 1266, 959, 816, 801, 735. Mass spectrum (m / z): 385 (M +), 383 (M +). Example 128 Production of 4,5-dihydro-2-isobutyl-6- (4-methoxyphenyl) -4 -methylamine formamidine-2H-pyridazin-3-one: In 2-iso Butyl-6- (4-methoxyphenyl) -4-methylamine formamidine-2H-pyridazin-3-one 50 mg (0.16 mmol) N, N-dimethylformamidine ( 10 ml) solution, 10% Pd / C 45 mg was added, and contact reduction was performed at 80 ° C. After 14 hours, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel chromatography (developing solvent: hexane / ethyl acetate (1/1)), and then the residue was extracted from chloroform-hexane. The title compound was crystallized as colorless needles (22 mg, 43.7%). Melting point: 124.2-125.0 ° C ^ -NMRCCDCls) (5: 0.926 (3H, d, J = 6.8Hz) 50.932 (3H, d , J = 6.8Hz), 2.07 · 2 · 24 (1Η, m), 2.82 (3H, d, J = 4.6 Hz), 3.05-3.17 (1H, m), 3.33,3.44 (2Η, m) 5 3.65-3 · 70 (2Η, m), 3.85 (3H, s), 6.93 (2Η, d, J = 9.0 Hz), 7.36 (1Η, br), 8.24 (2H, d, J = 9.0 Hz). IR (KBr) cm'1: 3392, 3015, 1675, 1646, 1515, 1405, 1364, 1256, 1177, 1026. Mass spectrum (m / z): 317 (M +). Examples 129 -105 -This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) 1241295 A7 B7 ------__________ V. Description of the invention (102) 2-Cyclopropylmethyl 4- (3-fluoro-4- Methoxyphenyl) -4 -Methionamine Methenyl-211-pyridone-3 -one Production: 2-Cyclopropylmethyl-6- (3-fluoro-4-methoxyphenyl) -4 -Methylamine formyl-2H-pyridazin-3-one 133 mg (0.40 mmol) Of toluene (1〇 ml), was added

Lawesson's reagent 162 mg (0.40 mmol) was stirred at 85 ° C under argon for 12 hours. The toluene was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (silica gel 6 g, hexane / ethyl acetate (4/1 ~ 2/1), and then subjected to chloroform-ethyl acetate). Crystallization yielded 109 mg (78.4%) of the title compound as orange needle crystals. Melting point: 178.0-178.5 ° C ^ -NMRCCDCls) (5: 0.47-0.63 (4H, m), 1.4 (M.47 (1H, m), 3.39 (3Η, d, J = 4.9 Hz), 3.96 (3H, s) 5 4 · 20 (2Η5 d5 J = 7.3 Hz), 7.03-7 · 08 (1Η, m ), 7.61 · 7 · 64 (1Η, m), 7.68-7.72 (lH, m) 5 9.26 (1H, s), 12.34 (1H, br) o IR (KBr) cm · 1: 3111, 1641, 1548, 1521, 1506, 1425, 1289, 1267, 1117, 1015. Mass spectrum (m / z): 347 (M +). Example 130 2-isobutyl-6- (4-methoxyphenyl) -4 · Production of Methionamine Methanyl-2H-pyridazin-3-one: 2-Isobutyl-6- (4-methoxyphenyl) _4_methylamine Methionyl-2Η-pyridazin-3 · Ketone as raw material was treated in the same manner as in Example 12 9 to obtain the title compound with a yield of 27.7%. Orange needle crystals (ethyl acetate-ether) -106- This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 1241295 A7 B7 V. Description of the invention 103. Melting point: 116.0-116.6 ° C ^ -NMRCCDCls) 5: 1.00 (6Η, d, J = 6.6 Hz), 2.36 (1Η, sep ·, J = 6.8 Ηζ), 3.38 (3Η , D5 (4.9 Hz), 3.87 (3H5 s), 4.17 (2Η, d, J = 7_3 Hz), 7.00 (2H, d5 J = 8.8 Hz), 7.85 (2Η, d, J = 9.0 Hz ), 9.28 (1H, s), 12.40 (1Η, br) 〇IRCKBiOcnT1 ·· 2960, 1640, 1544, 1515, 1503, 1266, 1249. Mass spectrum (m / z): 331 (M +) Test example 1 ( Inhibition of interleukin _ 1/3) Cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum (FBS) for 4 days, using confluent cultured HL-60 cells. Centrifuge HL-60 cells and remove the supernatant 'The cells were floated in RPMI 1640 medium with 3% FBS to make 1 X 106 cells / ml, and lipopolysaccharide was added to make the final concentration of 10 μg / ml, and 1 ml of each well was seeded in 2 4-well culture dishes. . One microliter of the test compound 'was added to each well for 3 days. After 3 days, the amount of interleukin-1 in the culture solution was measured by ELISA. The IC50 value was calculated by comparing it with the amount produced when no drug was added. The results for representative compounds are shown in Table 1. -107- This paper size is applicable

Hold

Line Standard (CNS) A4 size (210X297 mm) 8 1241295 5 Description of the invention (104

Table 1 I-Interleukin-1-produced compounds-Π7-Ί β- 0.038 0.31 0.11 0.05 0.53 0.387 0.40 29 46 > 100 31.6 61 63 66 87 111 112 128 Comparative Compound 1 Comparative Bismuth 2 Comparison Compound 3 is lighter than bismuth 4 (Comparative Compound 1)

'CH2CH2Ci (Comparative Compound 2) OMe

ch2ch2〇h (Comparative Compound 3)

(Compared to compound 4)

-108- — ， 丨 丨 丨 丨 —-This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 1241295 A7 B7 V. Description of the invention (105) As can be understood from Table 1, the compound of the present invention Compared with the compounds described in EOR. J. MED. CHEM., 1979, 14, 53-60, it is clear that the compounds have a superior effect of inhibiting the production of IL-1 / S. Industrial Applicability The pyrene derivative (1) or a salt thereof according to the present invention has a superior effect of inhibiting the production of interleukin-1 / 3, and is used for immune system diseases, inflammatory diseases, ischemic diseases, etc. Preventive and therapeutic agents. -109- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

In the formula, R represents a CKC0 alkoxy group, a crC6 alkylthio group, or a halogen atom; R2 represents a fluorene atom, a CVQ alkoxy group, or a halogen atom; ... table. · ^ Or straight or branched alkyl groups or (: 2 {9 straight or branched alkyl groups, depending on the case, may be based on a radical, a halogen atom, a cyano group, a CrC6 ring alkyl group, or a u group Phenylene or pyridyl substituted by a halogen atom, nitro, amine, or pyridylcarbonyl, or substituted by CVQ alkyl, hydroxy Crc0 alkyl, pyridyl € 1 &lt; 6 alkyl or CrC0 alkylthiophenyl Carbamoyl group substitution; R4 epicarboxyl group, Ci_G alkoxycarbonyl group, carbamoyl group which can be substituted by Cl-C6 alkyl, phenyl, pyridyl or phenyl Cr C6 alkyl or pyridyl crco alkyl Wide c 6 alkylthiomethane, may have a hepta-6 alkoxycarbonyl, phenyl C1-C6 alkoxycarbonyl or crC6, fethiophenyl crC6 alkoxycarbonyl, crC5 fluorenyl, Ci-C6 alkyl, fencyl Alkyl, pyridyl.]-. Alkyl or CrC6 alkylsulfonyl amine group or urea group which may have CrC6 pit group; the combination between the 4th and 5th position of the dotted table is a single or double bond. 2 · Pyridazine derivatives or their salts according to item 丨 of the scope of patent application, in which the 4- and 5-position C of the dotted line in the general formula (1) is a double bond. 1241295 6. Scope of patent application A BCD • According to Shen The pyridazine derivative or the salt thereof according to the second item of the patent is 2-isobutyl-6- (4 · methoxyphenyl) -4 · methylaminomethylmethyl-2H-pyridazinone, 2_ ( Cyclopropylmethyl) -6- (4-methoxyphenyl) -4-methylaminomethylammonium · 2Η_phyzine · 3 · ketone, 2- (cyclopropylmethyl) -6- (3-fluoro · N-methoxyphenyl) _4_methylaminomethylmethyl group · 2 Bipyridazinone, 2_ (Cyclopropylmethyl &gt; 'ethylaminomethylmethyl group_Heart (4_methoxyphenyl) -2Η- Pyridazin-3-one, 2- (4-chlorocinnamyl) -4-ethoxycarbonylamino-6_ (4 · methoxyphenyl) -2H-pyridazine · 3 · ketone, or 2- (4- Chlocinnamyl'formamidine · 6_ (4-methoxyphenyl) -2H-pyridazin-3-one. 4 · A pharmaceutical composition with an inhibitory effect on the q-point production of interleukins. The suazine derivative or the salt thereof according to any one of the patent scopes 1 to 3 is an active ingredient. 5. The pharmaceutical composition according to the fourth scope of the patent application, which is an immune system disease, a psychiatric disease, a deficiency Preventive and therapeutic agent for blood diseases, osteoporosis or sepsis 6. 6. The pharmaceutical composition according to item 4 of the scope of patent application, which is for the prevention of rheumatism, arthritis or inflammatory colitis Therapeutic agents of the scale it financial paper material B family mesh (&amp;) Zweig (21 ()> <tear Like male)